Podcasts about Ecog

JCO Editorial Fellow Peter Li and JCO Associate Editor Eileen O'Reilly discuss the ASCO 25 Simultaneous Publication paper "Tumor-Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, and I'm joined by JCO Associate Editor Dr. Eileen O'Reilly to discuss the Journal of Clinical Oncology article and abstract presentation "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Now, let's start with the relevance of the article. Eileen, can you explain this study to our listeners? Dr. Eileen O'Reilly: Thanks very much, Peter, for the invitation today to discuss this. Yes, so this is a positive phase 3 trial that was conducted in locally advanced, unresectable pancreas cancer. Patients were randomized to receive either gemcitabine and nab-paclitaxel, international standard, with or without tumor-treating fields. And this is a device like a battery pack that you would wear with a goal to wear that approximately 18 hours a day. And the primary endpoint of this study was overall survival, with key secondary endpoints of tumor response, progression-free survival, looking at pain-free survival, and distant progression-free survival. So, the primary endpoint was met with a median overall survival of 16.2 months compared to 14.2 months on the intervention versus control arm, with a hazard ratio of 0.82. And so that met the pre-specified boundary. There was not an increase in progression-free survival, but there was an increase in control of pain on the tumor-treating fields study. So, it was a large, global study, community, academic sites, randomized 570 people, and it supports what I think we've seen in other difficult-to-treat malignancies using tumor-treating fields, that there's a signal of interest. Dr. Peter Li: Can you speak to some of the strengths and weaknesses of this study? Dr. Eileen O'Reilly: So, strengths: it was a large study. It included community sites, it included academic sites. It included ECOG performance status 0, 1, and some patients with 2. The intent was locally advanced. It probably is fair to say that there were some patients who had more advanced disease based on early progression, based on relatively high CA 19-9 for a percentage of people. But likely that was, with random assignment, that would have presumably fallen out between the arms. The inclusion of patients with a lower performance status is nice to see in large phase 3 studies in pancreas cancer. So, they would be some of the strengths. So maybe some of the limitations are the fact that it's an open-label study - so, always some biases inherent in that. Acknowledging that the primary endpoint was overall survival, presumably that wouldn't be directly influenced by that. And there was an imbalance of women on the control arm, and women do fare a little better in this disease, so possibly kind of weighted one of the study arms a little bit. But nonetheless, I think it was a rigorously designed and rigorously conducted phase 3 trial. It's always hard to fully interpret the signal in locally advanced disease because of the fact that some patients go on to surgery, some patients have a treatment switch of cytotoxic therapy, some patients will go on to radiation. And the endpoint here of overall survival, to a degree, eliminates some of that. So, the benchmark, I think, was generally high here. Dr. Peter Li: Gotcha. And then with these findings and this positive study, how do you foresee this research being implemented and how it will impact clinical practice moving forward? Dr. Eileen O'Reilly: I think there'll be an educational need to introduce this approach to the community and to the pancreas cancer world. Again, there's a precedent in glioblastoma and data from other diseases, so there's some familiarity with this. I think people always want to understand how it works and why it works, and that's something that we'll look forward to hearing more about mechanistically, and also seeing how it can be built upon. And there's some intriguing data with the combination of tumor-treating fields and immunotherapy that's being evaluated in the PANOVA-4 study. So, we'll stay tuned to hear how that reads out in due course. But I think overall, it'll be educational and learning, managing the cutaneous impacts or some skin irritation effects from this, and building on this signal in locally advanced disease. Dr. Peter Li: Well, thank you so much, Eileen, for your time and for speaking about the JCO article, "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

Scientists have been poking around in the human brain again… and this time, it might end with talking toasters, telepathic Wi-Fi, and your Amazon Echo placing orders if you as much as daydream.Read the article: https://weirddarkness.com/makingrobocop/WeirdDarkness® is a registered trademark. Copyright ©2025, Weird Darkness.

Dr. Chris Holsinger shares the new guideline from ASCO on transoral robotic surgery (TORS) for patients with oropharyngeal squamous cell carcinoma. He reviews the evidence-based recommendations on baseline assessment, the role of TORS in HPV-positive and HPV-negative disease and in the salvage/recurrent setting, which patients are eligible or ineligible for TORS, and the role of adjuvant therapy. He discusses the importance of multidisciplinary collaboration and shared decision-making between patients and their clinicians. Read the full guideline, “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.”   TRANSCRIPT This guideline, clinical tools, and resources are available at asco.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology.   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.    My name is Brittany Harvey and today I'm interviewing Dr. Chris Holsinger from Stanford University, lead author on “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.” Thank you for being here today, Dr. Holsinger. Dr. Chris Holsinger: Thanks, Brittany. We've been working together for years on these guidelines and what a pleasure to get to meet you at least virtually today. Brittany Harvey: Yes, it's great to have you on. And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Holsinger, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So let's jump into this important guideline. Dr. Holsinger, to start us off, can you provide an overview of both the scope and purpose of this guideline? Dr. Chris Holsinger: Absolutely. And again, thanks for the opportunity to be here, Brittany. I appreciate the invitation to participate in the ASCO Guidelines and to work with the great people on this paper that's now out there. I think it's a really important guideline to be published because it really talks about surgery, specifically transoral robotic surgery, a minimally invasive technique, as a new way to treat head and neck cancer. Why that's so important is that what is now known as head and neck cancer is completely different than what we saw even 25 years ago. Around the turn of the century, some really thoughtful epidemiologists working at Hopkins and UW in Seattle started to see this connection between the human papillomavirus and head and neck cancer. And since then we've seen this precipitous rise in the number of throat cancers specifically due to HPV. The results from the American Cancer Society showed last year that head neck cancer, in particular these cancers of the oropharynx, actually were one of the few cancers that still had an increasing incidence, I think it was around 2.5% per year. And other studies have shown that almost 50% of the cases we're seeing across the United States now are actually HPV-mediated throat cancers. That's bad news because we're seeing this rise in cases, but it's good news in the sense that this is a cancer that is highly curable and I think opens up a lot of different treatment avenues that we didn't have a couple of decades ago. And when patients are facing a mortality risk that's two or three times lower than the formerly HPV-negative smoking-driven cancers, it really behooves us as clinicians, as oncologists to think about treatment selection in a completely different way. And for years, the only function-sparing option, surgery certainly was not, was radiation therapy with concurrent cisplatin chemotherapy. In 2009, the FDA approved the use of surgical robotics using a transoral approach, a minimally invasive approach to resect the primary tumors and to perform neck dissection. And so now when patients walk in the door, they not only have this gold standard option in the path of radiation therapy with chemo, but also frontline surgery. And with some recent publications, especially the ECOG 3311 study, there's some really good evidence that for HPV-mediated throat cancers, we can actually de-escalate the intensity of adjuvant therapy when we start with surgery first. So who we choose that option for, which patients want that option - these are all really important new questions that we try to grapple with in these guidelines. Brittany Harvey: That background is really key for setting the stage for what we're about to talk about today. And so next I'd like to review the key recommendations across the clinical questions that the panel addressed. So you just talked about the importance of treatment selection. So to start that off, first, what is recommended for baseline assessment for patients with oropharyngeal squamous cell carcinoma who are being considered for transoral robotic surgery? Dr. Chris Holsinger: So I think here we tried in the guidelines to really standardize the workup and approach of this disease, in general, but with a strong focus on who might be a good surgical candidate. As I mentioned in the introduction, I mean, this is a disease that is very new. Our workup is in flux. And so what we tried to do, especially in items 1.2 and 1.3, is to really standardize and confirm that the tumor that we're dealing with, which oftentimes presents in a metastatic lymph node, is in fact associated with the human papillomavirus. So how biopsy is done, how high risk HPV testing is performed, whether you're doing that with an in situ hybridization, a DNA based study, or a p16 immunohistochemical study. And we try to tackle these issues first to really make sure that the patient population we're considering is actually indeed eligible for this kind of treatment de-escalation with surgery. Brittany Harvey: Understood. So it's important to consider which patients could be eligible for TORS upfront. So what is the role of TORS in patients with HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Yeah, exactly. So I think first of all, surgery is ideally suited, and the robot is FDA approved for early-stage cancers - T1 and T2 cancers that are amenable to a minimally invasive approach. And we really try to emphasize, especially in our patient selection section of the guideline, who is really an ideal candidate for this. It's not just the T1 and T2 tumor. It's a tumor that is lateralized so that we can maybe consider managing the neck concurrently just on the side of the tumor, rather than doing bilateral neck dissection for most patients. Which patients might get the best functional outcome is a really critical component of this. And in fact, that actually goes back to a guideline that we didn't have time to chat about earlier, which is that we think every head neck cancer patient, whether or not they're being considered for transoral robotic surgery or frontline radiation therapy with cisplatin, every patient should have a pre-treatment assessment by a speech and swallowing expert. They're called different names across the country: speech language pathologists, speech pathologists, etc. But having a really good functional assessment of the patient's ability to swallow before treatment selection is really critical. And why that's important with frontline surgery is that there's a period of about one or two weeks after which that patient really needs intensive rehabilitation. And so for every patient being considered by TORS, we want to work really hand in hand with that speech pathologist to do pre-habilitation and then immediate post-operative rehab and then long longitudinal rehabilitation so that if radiation is needed down the road in a month, that patient just hopefully sails through this de-escalated treatment that we're offering. Brittany Harvey: Great. I appreciate you describing which patients can be considered for transoral robotic surgery. So beyond that, which patients with HPV-positive oropharyngeal squamous cell carcinoma aren't really good candidates for TORS? Dr. Chris Holsinger: We talked about that sort of ideal patient, but you know, we're not always living in an ideal world. And so I think it's important, and I'm really happy about the multidisciplinary discussions that led to these final guidelines because I think it helped engage radiation oncologists, medical oncologists, and surgeons around who's maybe not a good candidate for this because radiation therapy, with or without cisplatin chemotherapy, remains a good option for many of these patients. But I think the consensus, especially among the surgeons in this group, were that patients with tumors were more endophytic - that's the old fashioned oncology and surgical oncology term that refers to tumors that seem to not be as evident on the surface and have more of an infiltrative deep growth pattern - these are not ideal tumors. Whereas an exophytic tumor that's growing upwards, that's more readily seen on flexible endoscopy during a routine clinic assessment, or frankly, better seen on imaging, those exophytic tumors are better suited to a surgical approach because the surgeon has a better chance when he or she sees the tumor to get a good margin. When we can appreciate not just the surface mucosal margins that need to be taken, but also have a better chance to appreciate their depth. And with those infiltrative tumors, it's much harder to really understand how to get that deep margin, which in many cases is always the hardest. And so that's a long way to say that surgical decision making, patient selection is really critical when it comes to offering TORS as a multidisciplinary group. And then there are a few other things that we can quickly talk about before we move on to discussing adjuvant therapy. But I think there are some relative contraindications to patients who might have tumors arising in a palatine tonsil or tonsillar pillar, but which might grow significantly into the soft palate, such that a major palatal resection would be needed to get a good margin. For T1 and T2 tumors, we're not sure that that is an ideal candidate. And the other relative contraindication, but it's a hard and fast contraindication in my personal practice, is patients with extensive nodal disease. I think a patient who has preoperative extranodal extension, matted nodes, clinically and on MRI, you know pre-op they're going to need intensive post operative concurrent chemoradiation post-op that's maybe not the best patient for TORS, although there are some select cases where that that might make sense. But that's a quick overview of patient selection for TORS, Brittany. Hopefully, that's helpful. Brittany Harvey: That's definitely helpful. I think it's really important to consider not only who is eligible, but who isn't eligible for this de-escalation of treatment, and I appreciate you clarifying some of that. So then you've just also mentioned adjuvant therapy along with multidisciplinary discussion. So what is recommended regarding adjuvant therapy for patients who have resected HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Definitely. And I think the post-operative discussion has to begin with great pre-op planning. And pre-op planning is really anchored in a really robust multidisciplinary team. So, we spoke earlier about the critical importance of getting speech language pathology involved initially, but they're part of a much larger team that includes not just a surgeon, but medical oncologist, a radiation oncologist and a dental oncologist - all of these specialties, and I could think of several others if we had time to chat further - this should also be really engaged in the care of these patients. But great decision making regarding adjuvant therapy really begins with a robust multidisciplinary consultation pre-op and we try to emphasize that in the guidelines. But just to return and answer your question very directly, I think adjuvant therapy is really the critical piece in getting that great functional outcome for a patient with HPV-mediated throat cancer. And I think traditionally patients who have a variety of different risks, based on a large study done again by the ECOG group, ECOG 3311, we showed that by stratifying patients based on their surgical pathology rather than on an estimate of disease extent, we can better stratify adjuvant therapy. And so the low risk patient is a patient with good margins and of course, good margin, we could spend another two hours discussing that. But good margins are greater than at least 1 to 3 millimeters superficially and a clear deep margin. Patients with lymph node metastases that are less than 3 cm and a single lymph node can sometimes be observed but most patients don't fall into that low risk category. Most patients fall into an intermediate risk where the margin is good and it's clear, but it might be close. That depends if you're talking about the superficial mucosal margin or the deep. But more often than not, we spend a lot of time considering the extent of lymph node involvement as it pertains to how adjuvant therapy is delivered. And I think for patients with less than 4 lymph nodes traditionally without extranodal extension, radiation therapy will suffice for adjuvant therapy after TORS. And the question of dose then comes up. Are we talking 50 Gray, the experimental arm that showed real promise in the ECOG 3311 trial, or 60 Gray or more traditional dose? And that is a topic definitely for another podcast, which we should do with a radiation oncologist online. I don't want to get into the weeds with that, but I refer you to our guidelines and Bob Ferris and Barbara Burtness' paper from JCO in 2021 for further details about that. But then for patients with positive margins with more than four lymph nodes, but especially patients with extranodal extension, the role of radiation therapy and chemotherapy is really absolutely critical. Because these patients and while they only accounted for around 20% to 30% of patients that we're seeing in this new era of TORS, they're the ones that we're really focusing on how can we do better because their overall survival is still good, it's 90%, but it's not as good as the patients we're seeing with a low and intermediate risk. So that's a brief overview there. Brittany Harvey: I appreciate that overview. And yes, we'll refer listeners to the full guideline, which is linked in the show notes of this episode to learn more about the intricacies of the radiation therapy that you mentioned. So then we've talked a lot about patients with HPV-positive disease, but what is the role of TORS in patients with HPV-negative disease? Dr. Chris Holsinger: I think TORS still has a role for these patients. Our colleague in India, Surender Dabas, has a really nice series that shows that for HPV-negative patients, this is a way for early stage cancers to potentially escalate the intensity of treatment for a disease that does worse than this new HPV-positive we're seeing in the US. So I think there's a good signal there. I think more study needs to be done and I think those studies, in fact, are underway in India and other countries. I hope that we can, as an oncology community here in the United States, also tackle this disease, which is still a significant part of the disease we face in head and neck oncology. Brittany Harvey: Yes, we'll look forward to more data coming out for HPV-negative disease. So then, the last clinical question that the guideline panel addressed: What is the role of TORS in the salvage or recurrent setting? Dr. Chris Holsinger: So we wrap up the guidelines tackling this topic. It's definitely something for the experienced TORS surgeon in consultation with that multidisciplinary team. Oftentimes, we are still seeing many patients who need salvage surgery and I think, while TORS alone could be a really effective treatment option, TORS with a microvascular reconstruction is oftentimes what is needed for these patients who, with recurrence, do often present with an RT 2, 3, 4 tumor. In my own practice, I found that using TORS as a way to minimize the superficial mucosal extent and then delivering that tumor through a traditional lateral pharyngotomy, then neck dissection and then having a microvascular flap inset done after that really provides the best possible chance for good long term function and of course control of the tumor. Here, I definitely refer the listener to some great work done out of the Royal Marsden with Vin Paleri, who we're happy to have on our TORS guideline panel for his RECUT study that really grapples in some detail with these very issues. Brittany Harvey: Excellent. And so we've covered a lot of the recommendations here that were made by the panel and you've touched a little bit about how this changes things for clinicians in practice. But what should clinicians know as they implement these new recommendations? Dr. Chris Holsinger: One thing as we close, I hope that in the future we can really start to grapple with this concept of patient selection. I think these guidelines help establish that TORS is a great oncologic option with - really the only option for treatment de-escalation in the here and now. Radiation therapy and cisplatin concurrent chemotherapy is going to be an option that is such an important choice for patients. And I think where I hope the field goes in the future is figuring out which patient wants one of these options. And I think certain patients really want that tumor taken out and others just the idea of surgery is not something that makes sense for them. How we in the context of a multidisciplinary team, really engage that patient, elicit their treatment preferences and then through considering treatment eligibility criteria that we've spelled out here for surgery and can be spelled out for chemo RT, bringing all that together in a formal shared decision making process is really where I hope the field will be going in the next few years. And hopefully these guidelines help to pave the way there. Brittany Harvey: Definitely the aspect of care by a multidisciplinary team and talking with patients to go through shared decision making is key to implementing these guidelines. So then, in that same vein, what do these recommendations mean for patients with oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: I think the central take home message for patients should be that especially if you have a T1 and T2 tumor, it's really important to have that consultation with a surgeon who knows how to do TORS and has a busy practice, but then also having an honest discussion up front about what the functional outcomes would be both with surgery and also chemo RT. And I think just knowing all those different options, that multidisciplinary treatment selection process is going to be that much more robust. And I think more right decisions will get made and we'll see less decisional regret down the road, which I think is a long term goal of our field. Brittany Harvey: Absolutely. That discussion of preferences is key. So then to wrap us up, you touched on this a little bit earlier in talking about ongoing research and data, particularly in the field of HPV-negative disease, but what are the outstanding questions regarding TORS in this patient population? Dr. Chris Holsinger: Yeah, I think that in addition to this work around shared decision making, I really hope that we'll embrace shared decision making in the context of future clinical trial. I think where we are now is you have surgeons saying, “Hey, TORS and 50 gray is a great option. Why aren't we doing that?” And then our colleagues, perhaps across the aisle, if I can use a political metaphor, are saying, “Well, where's the comparative data? Can we even do a randomized clinical trial between surgery and radiation?” Well, Christian Simon in Lausanne in Switzerland is trying to do this in a small pilot study being led by the EORTC, and I would encourage American investigators to consider something analogous. But I think how we solve this question of I think treatment choice is going to be pivotal for any such trial to ever be done. And then finally, I think, how will the changing treatment landscape around immunotherapy change this? There's some really provocative data that dates back to 1996 in a JCO paper from Ollivier Laccourreye and the University of Paris experience that showed induction chemotherapy followed by function preserving surgery in the larynx was a really powerful strategy for organ preservation, and that has never been followed up in the United States. And so especially with the upcoming presentation of KEYNOTE-689, will we be doing neoadjuvant approaches for patients and then following them by minimally invasive surgery or lower dose radiation? I think these are going to be some exciting new areas of study and I can't wait to see how this might evolve so we can refine the treatment - still get those great outcomes, but reduce those late toxicity. Brittany Harvey: Yes. We'll look forward to this ongoing research to continue to move the field forward. So, Dr. Holsinger, I want to thank you so much for your time to develop this important guideline. It's been great to have you on the podcast to discuss it today. Dr. Chris Holsinger: Well, thanks a lot Brittany. It's nice to finally meet you. Brittany Harvey: Likewise. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   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.

Featuring perspectives from Dr Heather Wakelee, including the following topics: Introduction (0:00) Cases: A man in his late 50s with metastatic carcinoma of the lung, no actionable genomic alteration (AGA), PD-L1-negative, and a man in his early 60s with metastatic squamous cell carcinoma of the lung, PD-L1-negative — Brian P Mulherin, MD and Taral Patel, MD (8:08) Case: A man in his late 60s presenting with metastatic adenocarcinoma of the lung, multiple bone metastases, no AGA; PD-L1 20%; enrolled on ECOG-EA5163 — Priya Rudolph, MD, PhD (21:45) Current and Emerging Immunotherapeutic Strategies for Metastatic Non-Small Cell Lung Cancer (mNSCLC) (30:55) Case: An African American man in his early 60s with 6.2-cm squamous cell carcinoma of right upper lung receives neoadjuvant treatment as per CheckMate 816 — Dr Rudolph (39:16) Case: A man in his late 60s with pT2aN0 invasive adenocarcinoma of the right lower lung, no AGA; PD-L1 5% — Zanetta S Lamar, MD (44:57) Antibody-Drug Conjugates and Other Management Approaches for mNSCLC without AGAs (48:51) Case: A woman in her early 60s diagnosed in 2014 with metastatic adenocarcinoma of the lung treated on ECOG 5508 (carboplatin/paclitaxel/bevacizumab) receives nivolumab on disease progression — Dr Rudolph (56:35) CME information and select publications

Send us a textUnlock the mysteries behind dizziness, vertigo, and lightheadedness with renowned experts Dr. Douglas Beck and Dr. Joseph Sakumura. Join us as we explore how the different sensations of movement can reveal underlying vestibular disorders. Dr. Sakumura details the critical role of nystagmus in differential diagnosis, guiding us through the nuanced process of identifying whether a vestibular disorder is peripheral or central, and how the direction of nystagmus can indicate the affected ear.Discover the nuanced differences between vestibular neuritis and Meniere's disease. We'll unpack how herpes simplex virus contributes to vestibular neuritis, leading to sudden and severe vertigo, in contrast to the recurring episodes of Meniere's disease. Our conversation also tackles the challenge of distinguishing these conditions from migraines, which often manifest with similar symptoms. Expect to gain a comprehensive understanding of the diagnostic hurdles faced by healthcare professionals in this complex area of vestibular health.Our final focus is on Meniere's disease and endolymphatic hydrops, exploring their shared symptoms and the diagnostic criteria from the Barany Society. Dr. Sakumura shares insights into the use of electrococleography (ECOG) for evaluating endolymphatic hydrops and discusses the intricate surgical approaches for Meniere's disease treatment. We also dive into the cautious prescription of vestibular medications like Meclizine, stressing the necessity for accurate diagnosis before treatment to ensure effective patient care. Tune in for an enlightening discussion that promises to deepen your understanding of these critical topics in vestibular health.While we know all hearing aids amplify sounds to help you hear them, Starkey Genesis AI uses cutting-edge technology designed to help you understand them, too.Click here to find a provider near you and test drive Starkey Genesis AI! Support the showConnect with the Hearing Matters Podcast TeamEmail: hearingmatterspodcast@gmail.com Instagram: @hearing_matters_podcast Twitter: @hearing_mattasFacebook: Hearing Matters Podcast

Most of what we have learned about the functioning of the living brain has come from extracellular electrical recordings, like the measurement of spikes, LFP, ECoG and EEG signals. And most analysis of these recordings has been statistical, looking for correlations between the recorded signals and what the animal/human is doing or being exposed to.   However, starting with the neuron rather than the data, these electrical brain signals can also be computed from biophysics-based forward models, and this is topic of this podcast. 

Welches Potenzial hat das bidirektionale Laden? Wie steht es um die Elektromobilität in Deutschland und der Welt? Und warum wollen Teile der Politik unbedingt am Verbrenner festhalten? Das und noch viel mehr haben wir Ex-Volkswagen-Konzernchef Herbert Diess gefragt. Der weltweit bestens vernetzte Automobil-Manager ist heute Verwaltungsratsvorsitzender bei The Mobility House. Das Unternehmen aus München verbindet seit 2019 die Automobil- und Energiebranche mit intelligenten Lade- und Energielösungen. Die Vision: zero emission und zero costs. Und genau dieses Ziel bekräftigt auch Herbert Diess: "Umsonst fahren ohne Emissionen – das ist wirklich möglich!" Bidirektionales Laden sei "wahrscheinlich der größte Hebel in der Energiewende" und eine echte "Wunderformel". "Die Zeit ist reif dafür", sagt Diess im Gespräch mit electrive-Chefredakteur Peter Schwierz. Schließlich fahre man im Elektroauto einen Großteil der Zeit "eine völlig überdimensionierte Batterie herum". Da liege es nahe, diese zu nutzen, rät Herbert Diess. Natürlich sei noch viel zu tun, doch das bidirektionale Laden sei jetzt nur noch ganz wenige Jahre vom Massenmarkt entfernt, ist Diess überzeugt. "Aber es erfordert natürlich Arbeit, auch politische Arbeit." Apropos Politik: Die sei, so Herbert Diess, bei der Elektromobilität im Europawahlkamp dem Populismus verfallen. Aus Angst, noch mehr Wähler an rechte Parteien zu verlieren, hätten sich Konservative und Liberale an den Verbrenner geklammert – und sich alternativer Fakten bedient. "Was wir jetzt erleben, ist eindeutig Populismus", sagt Herbert Diess. Er habe deshalb vollstes Verständnis für verunsicherte Kunden, die jetzt doch wieder am Elektroauto zweifeln. Die Debatte um Technologieoffenheit und ein Aufheben des Verbrenner-Aus in Europa ordnet der Ex-VW-Chef so ein: "Das kann man schon machen und es ist vielleicht volkswirtschaftlich gar nicht so unsinnig, weil man natürlich damit auch eine sehr ertragsstarke Industrie schützt." Es seien nicht nur die Autohersteller und Zulieferer, sondern auch die Tankstellen. Oder wie Diess es formuliert: die ganze fossile Kraftstoffindustrie. "Je länger des profitabel lebt, desto länger werden Steuern bezahlt. Man muss nur aufpassen, dass man dann eben die Zukunft nicht verliert." In der Folge – und auch verbunden mit der Haushaltskrise – habe Deutschland aber genau diesen Anschluss gerade verpasst. "Der Leitmarkt für Elektromobilität ist jetzt sicherlich China", so Diess. Und das sei die Tragik der aktuellen Entwicklung. "Das ist die Gefahr, wenn man zu lang an einer bestehenden, sehr erfolgreichen Technologie festhält, dass man die neue versäumt." Und doch räumt Herbert Diess der deutschen Automobilindustrie noch Chancen ein: Wer das nächste superschnell ladende und extrem leichte Premium-Elektrofahrzeuge baue, sei völlig offen. "Das kann gut BMW, Daimler oder auch Porsche oder Audi sein." Und er wirbt am Ende des Podcasts nochmal klar für das bidirektionale Laden und die konsequente Umsetzung dieser Technologie hierzulande. "Der Nutzen, den wir damit für den Kunden, aber auch für die Volkswirtschaft, für Deutschland stiften können, ist immens." Viel Vergnügen beim Hören! Diese Folge von "eMobility Insights" ist der Auftakt für eine kleine Sommer-Staffel rund um das bidirektionale Laden. Die Reihe umfasst vier Podcast-Folgen und wird Ihnen präsentiert von The Mobility House. In jeder Ausgabe kommen auch weitere Experten zu Wort. In diesem Fall ist das Jörg Heuer von EcoG, der erklärt, was die Interoperabilität beim bidirektionalen Laden rein praktisch funktioniert.

Alle relevanten Finanzierungsrunden, Übernahmen, Partnerschaften und weitere Erfolgsmeldungen aus dem Juni in einem Podcast: Der monatliche Newsflash in Episode 81 unseres Munich Startup Podcasts. Mit dabei: Crafthunt, Arx Robotics, Isar Aerospace, Hawk AI, Storybox, Eze Networks, Ecog, Planet A Foods, Navel Robotics, Exomatter, Vsquared Ventures, High-Tech Gründerfonds. Eine Link-Sammlung zu allen Meldungen findest Du übrigens im Artikel zur Folge: https://www.munich-startup.de/podcasts/newsflash-juni/ ---------- Mehr Infos zur Münchner Startup-Welt findest Du natürlich regelmäßig auf unserem News-Portal: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://www.munich-startup.de/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Übrigens: Je nachdem, welchen Podcast-Kanal Du nutzt, freuen wir uns natürlich auch über Likes, Bewertungen, Kommentare und mehr.

  Phil Starr is a Professor of Neurological Surgery at University of California, San Francisco and a developer of implantable brain devices. At UCSF, he co-directs a multidisciplinary neurology/neurosurgery movement disorders clinic together with Dr. Jill Ostrem. I've been a long-time admirer of Phil's work and in this conversation we blaze through quite a few of his numerous publications. One key breakthrough and invention of Phils work has been to include Ecog recordings – both intraoperatively but also chronically – to investigate brain signals in various states. We talk about the Open Mind Consortium, Mentorship and the cross-pollination between academia and industry. One key highlight of Phils work is a paper which was accepted for publication in Nature Medicine, at the time of recording this just yesterday. In it, the three co-first authors Carina Oehrn, Stephanie Cernera and Lauren Hammer demonstrate the chronic use of a newly identified cortical physiomarker, which is now referred to as the finely tuned gamma activity. I hope you enjoy this conversation as much as I did, and thank you for tuning into Stimulating Brains!

This episode, Bob and Randy welcome Bob Skinner, longtime Detroit IT veteran and the Managing Director of North America for EcoG. They discuss various aspects of the electric vehicle (EV) industry, including challenges with charging infrastructure, technological advancements, and the future of EVs. The conversation covers issues such as the role of the government in infrastructure, sustainability concerns, and innovations like highways that charge cars as they drive. They also touch upon personal anecdotes and the excitement surrounding new EV models.

Have you ever wondered if it's possible to give speech back to those who've lost it using advanced brain technology? Dear Listeners, welcome to episode #82 of our “Neurocareers: Doing the Impossible!” podcast, where we're diving deep into the world of speech neuroprostheses and exploring how brain-computer interfaces (BCIs) are unlocking new ways to communicate. Speech-decoding BCIs are gaining ground rapidly. They promise a new way to communicate for those who cannot speak by tapping directly into brain activity. The secret to making these devices work is understanding how speech is produced in the brain, from the timing to the specific brain regions involved. Interestingly, it looks like even deeper brain areas, including the insula, hippocampus, and thalamus are involved in this process. I am your podcast host Dr. Milena Korostenskaja or simply Dr. K. and joining us today is Maxime Verwoert, a researcher with the long-term goal of developing speech neuroprostheses. After her studies in Psychology and Neuroscience at Utrecht University, Maxime is now a PhD candidate at Maastricht University in Netherlands focusing on decoding speech signals in real-time with stereo-EEG. This technology is less invasive than other methods, such as ECoG, offering hope for long-term use in BCIs. Maxime's recent work, published in Nature's Scientific Data, involved collecting a rich dataset from participants reading aloud while their brain activity was meticulously recorded. This dataset covers a broad spectrum of brain regions and offers deep insights into how we produce speech. In our chat, Maxime explains how this cutting-edge technology is developed, the hurdles of interpreting complex brain signals into speech, and what the future holds for people needing speech neuroprostheses. Maxime will also share her advice for those who are planning to get into the field of neurotechnologies. Whether you're a tech enthusiast, a healthcare professional, or just curious about how neuroscience changes lives, this conversation promises to bring unique knowledge and inspiration. So tune in, and get ready to be amazed by how close we are to turning thoughts into words! About the Podcast Guest: Get in touch with Maxime Verwoert via LinkedIn: https://www.linkedin.com/in/maxime-verwoert-756966105/ Lab:  https://neuralinterfacinglab.github.io/ Dataset: https://osf.io/nrgx6/ https://www.nature.com/articles/s41597-022-01542-9 Articles: https://doi.org/10.3389/fnins.2020.00123 (sEEG for BCIs) https://ieeexplore.ieee.org/document/10394550 (sEEG semantics) https://www.nature.com/articles/s42003-021-02578-0 (sEEG speech BCI proof-of-concept) https://doi.org/10.1007/s13311-022-01190-2 (speech BCI review)  Courses: https://www.codecademy.com/ https://www.codecademy.com/ https://www.coursera.org/ https://scikit-learn.org/stable/  https://neuromatch.io/ Mental Health: “Feeling Great” Book (https://www.amazon.com/stores/page/E0B7C5D5-CD14-405B-BD0A-253F8D94A3B4?channel=db-website) “Feeling Good” Podcast (https://feelinggood.com/subscribe/)   About the Podcast Host: The Neurocareers podcast is brought to you by The Institute of Neuroapproaches (https://www.neuroapproaches.org/) and its founder, Milena Korostenskaja, Ph.D. (Dr. K), a neuroscience educator, research consultant, and career coach for people in neuroscience and neurotechnologies. As a professional coach with a background in the field, Dr. K understands the unique challenges and opportunities job applicants face in this field and can provide personalized coaching and support to help you succeed. Here's what you'll get with one-on-one coaching sessions from Dr. K: Identification and pursuit of career goals Guidance on job search strategies, resume, and cover letter development Neurotech / neuroscience job interview preparation and practice Networking strategies to connect with professionals in the field of neuroscience and neurotechnologies Ongoing support and guidance to help you stay on track and achieve your goals You can always schedule a free neurocareer consultation/coaching session with Dr. K at https://neuroapproaches.as.me/free-neurocareer-consultation Subscribe to our Nerocareers Newsletter to stay on top of all our cool neurocareers news at updates https://www.neuroapproaches.org/neurocareers-news   

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects. In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization. The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions. The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration. So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation. The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively. Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants. Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting. Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser. Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death. The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively. Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer. While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis. All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors. The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study. In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial. Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone. More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe. In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression. No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients. Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia. For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity. Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group. Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events. So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile. At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights. In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site. The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy. This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights.  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.    

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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. Guests' statements on this 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. ASCO's first clinical trial is the Targeted Agent and Profiling Utilization Registry, or TAPUR Study. This clinical trial is intended for people with advanced cancer without other treatment options available, and whose cancer has at least one genomic variation that can be targeted with specific drugs. In this podcast, Dr. Richard Schilsky discusses the TAPUR study and explains why it is significant. He also discusses what participants can expect. Dr. Schilsky is the Principal Investigator for the TAPUR study. He is also the former Chief Medical Officer for ASCO and Professor Emeritus at University of Chicago. View Dr. Schilsky's disclosures at Cancer.Net. Dr. Schilsky: Hi, everyone. My name is Richard Schilsky and I'm the principal investigator of the ASCO TAPUR Study and the former Chief Medical Officer of ASCO. I'm happy to give you an overview and update about the study today. By the way, TAPUR is an acronym that stands for Targeted Agent and Profiling Utilization Registry. Hopefully, the reason for naming it that will become clear as you listen. The TAPUR study was conceived in 2013 and launched in 2016, and was based on the observation that there was a rapid increase in testing the tumors of patients with advanced cancer for gene mutations that might be contributing to the growth of the tumor, so-called genomic profiling, in the hope of finding a genomic alteration that could potentially be treated by a drug that was already FDA-approved for a different tumor type than what the patient had. Meaning, in order for the patient to receive the drug, it would have to be prescribed off-label. The challenge with prescribing the off-label use of a drug is that most insurance plans don't cover the cost of treatment. Additionally, even if the patient were able to receive the drug, there was no mechanism for the oncology community to learn from the patient's treatment experience. The TAPUR study has managed to address these challenges by providing access to FDA-approved drugs at no cost to the patient and providing treatment results to the oncology community regarding the effects of off-label use of the treatments being studied. Now, TAPUR is a clinical trial, and its primary objective is to describe the anti-tumor activity and toxicity of commercially available targeted anti-cancer drugs prescribed for treatment of patients whose tumors have a genomic alteration known to be a drug target or to predict sensitivity to a drug. TAPUR was designed to be simple for providers and patients. It's a phase 2 study, meaning that we're aiming to learn about efficacy and safety. It's prospective, that is, it enrolls patients going forward. It is not randomized. Everybody gets a treatment based on the genomic profile of their tumor and the available treatments in the study. It's a multi-basket study. That is to say, multiple therapies are available on the study that are targeting multiple genomic alterations. And it's a pragmatic study. TAPUR attempts to replicate routine clinical care. It's exempt from FDA oversight. It provides oral drugs that can be shipped directly to the patient's home after the first visit. Now, as I said, the TAPUR study was launched in March of 2016. And as of this month, it's still going strong, with more than 2,700 patients having been enrolled at 267 locations in 28 states. So how does the study work? Well, a patient's physician has results of a genomic profile of the patient's tumor and determines that a study drug might benefit the patient. The patient then decides to participate in TAPUR and gives their informed consent. A molecular tumor board, which is a group of experts convened by ASCO, is available to consult regarding the proposed treatment or to provide alternative treatment options for the patient. A participating pharmaceutical company, and there are 10 right now, provides the study treatments at no cost to the patient. The patient is cared for by their own oncologist, receives a standard dose of the drug, and is evaluated at standard intervals to see if the treatment is working and if they're having any side effects. ASCO has convened an independent data and safety monitoring board of cancer experts that periodically reviews results and determines whether treatment is promising for a particular cancer type and genomic alteration. That's what we call a cohort in the study. Once the data are finalized, ASCO publishes the study findings in peer-reviewed journals to inform clinical practice and future research. So let me give you an example. There are specific molecular alterations that often appear in tumor cells that are important for driving the growth and progression of the cancer and can be targeted with specific drugs that interrupt those abnormal molecular pathways. Many of these alterations occur at low frequency, meaning in less than 5% of tumors of any given type. The benefit of the TAPUR trial having a basket design is our ability to evaluate multiple therapies simultaneously to target multiple low-frequency alterations, which ultimately offers more treatment options to patients who wish to participate in the study. If the TAPUR study were set up looking to target only a single genomic alteration, we would potentially have to screen hundreds of patients in order to find one who is appropriate for the trial, which also means hundreds more would still be left without treatment options. But because TAPUR evaluates multiple treatments and multiple genomic alterations simultaneously, we found that about two-thirds of patients who were screened for the trial ultimately enroll. A specific example of a drug and targeted gene alteration on TAPUR is the use of the treatment combination pertuzumab plus trastuzumab in tumors with ErbB2 amplification or mutation. Now, you may be aware that ErbB2 is a gene that is synonymous with the HER2 gene that is frequently amplified or overexpressed in patients with breast cancer. And this drug combination, pertuzumab and trastuzumab, is FDA-approved for treatment of patients with breast cancer. But in the TAPUR study, we found multiple tumor types outside the FDA-approved label that can benefit from this treatment if an ErbB2 alteration is detected, including patients with colorectal cancer, endometrial [uterine] cancer, biliary tract cancer, and lung cancer. To learn more about TAPUR, please follow our progress at the ASCO website. In an effort to provide up-to-date information about cohorts that are available for enrollment on the TAPUR study, ASCO launched a public-facing status report in March of 2023. So first click on www.tapur.org. Click on the link to the ASCO website. From there, select study participation at the bottom of the page. Once at the study participation page, click on the link to see a list of study cohorts that are currently enrolling. The report updates daily, providing viewers with an up-to-date list of available study cohorts based on their genomic alterations. It's important to note that study cohorts are available on a first-to-enroll basis. You can also find information about current results from the TAPUR study on the study results page. So what have we learned so far? Thus far, we've publicly reported results on 29 cohorts of patients. 17 gave a positive signal of treatment activity, 12 were negative. Now we feel it's just as important to report on the negative results as the positive results. If the treatment is unlikely to be effective for patients, it's important to inform the oncology community because all of the drugs in the study are commercially available and could be prescribed to a patient. Enrollment to patients on TAPUR is very representative of the U.S. population. The study has broad eligibility criteria that allows more patients to enroll, including patients with an ECOG performance status of 0 to 2 and younger patients. Some treatments allow for adolescent patients as young as age 12 to be enrolled in the study. We hope the oncology community finds value in the TAPUR study. Physicians have the opportunity to contribute to research and participate in publications and to contribute more knowledge in the field of oncology. TAPUR provides guidance on interpreting genomic reports via the molecular tumor board and provides additional treatment options for patients. Institutions obtain insights on potential new uses of existing drugs and their side effects, and TAPUR data can inform updates to clinical practice guidelines. And patients receive access to drugs not available as standard of care. Patients may be able to receive oral drugs at their home and limit their commute to clinic. And of course, participation in the study provides an opportunity for patients themselves to contribute to knowledge about cancer treatments. To find a clinical site offering the TAPUR study, please visit the TAPUR website again, www.tapur.org and select “Participating Centers.” This will lead to a searchable map of participating sites and includes the site-specific contacts. Contact the primary contact listed for that site. Thank you for listening to this update on the ASCO TAPUR study and enjoy the rest of your day. ASCO: Thank you, Dr. Schilsky. Learn more about clinical trials, including the TAPUR Study, at www.cancer.net/clinicaltrials. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

La Dra. Florencia Cuadros, oncóloga clínica del Hospital Eva Perón, y el Dr. Matías Chacón, oncólogo médico adscrito al Instituto Alexander Fleming ambos de Argentina, nos hablan sobre los estudios más relevantes en melanoma presentados durante ESMO 2023: Estadios tempranos SWOG 1801: estudio aleatorizado, fase II de pembrolizumab adyuvante vs. pembrolizumab neoadyuvante en pacientes con melanoma en estadio IIIB clínicamente detectable y estadio IVC que era susceptible de resección quirúrgica. El objetivo primario fue la supervivencia libre de eventos (SLE) en la población por intención de tratar. KEYNOTE-942: estudio abierto, aleatorizado, fase II, evaluó si la terapia adyuvante posoperatoria con mRNA-4157 y pembrolizumab mejoró la supervivencia libre de recurrencia (SLR) en comparación con pembrolizumab solo en pacientes con resección completa del melanoma cutáneo y un alto riesgo de recurrencia en estadio IIIB/C/D y IV. Estadios avanzados SECOMBIT: estudio fase II,  no comparativo, aleatorizado, de tres brazos, para pacientes con melanoma metastásico con mutación BRAF V600 no tratado, que fueron asignados aleatoriamente al grupo A (encorafenib + binimetinib hasta progresión de la enfermedad, seguido de ipilimumab + nivolumab), grupo B (ipilimumab + nivolumab hasta la progresión de la enfermedad, seguido de encorafenib + binimetinib), o grupo C (encorafenib + binimetinib seguido de ipilimumab + nivolumab hasta la progresión de la enfermedad seguida de encorafenib + binimetinib). CheckMate 204: estudio fase II, multicéntrico, abierto, incluyó a pacientes adultos (edad ≥18 años) con melanoma de metástasis cerebrales medible (0.5–3.0 cm de diámetro). Los pacientes asintomáticos (cohorte A) tenían un ECOG de 0 o 1 y no tenían síntomas neurológicos, ni uso inicial de corticosteroides; los pacientes sintomáticos (cohorte B) tenían un estado funcional ECOG de 0 a 2, con síntomas neurológicos estables y podrían estar recibiendo dosis bajas de dexametasona. NIBIT M2: estudio fase III, reclutó a pacientes >18 años con melanoma BRAF mutado y metástasis cerebrales activas, asintomáticas y no tratadas, aleatorizados (1:1:1) a fotemustina o ipilimumab + fotemustina o ipilimumab + nivolumab. TACo-BEAT-MBM: estudio fase II, que evaluó qué tan bien funcionaba bevacizumab y atezolizumab con o sin cobimetinib en el tratamiento en pacientes con melanoma no tratado que se ha diseminado al cerebro. NCT03025256: estudio fase I/Ib, para pacientes >18 años con melanoma metastásico y evidencia de enfermedad leptomeníngea por resonancia magnética y/o citología del LCR, ECOG PS ≤2 , que fueron tratados de forma simultánea con nivolumab intratecal e intravenoso. Se permitió el tratamiento concurrente con inhibidor de BRAF/MEK y dexametasona ≤4 mg/día. IMCgp100-202: estudio abierto, fase III, aleatorizados al azar, en pacientes con melanoma uveal metastásico positivo para HLA-A*02:01 no tratados previamente en una proporción de 2:1 para recibir tebentafusp o la terapia elegida por el investigador con un solo medicamento, pembrolizumab, ipilimumab o dacarbazina, estratificados según el nivel de lactato deshidrogenasa.

Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care." TRANSCRIPT The guest on this podcast episode has no disclosures to declare.   Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. And this is where we get in-depth on manuscripts and editorials that have been published in the Journal of Clinical Oncology. As always, I am your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the Journal of Clinical Oncology, and I'm so excited to be here today. We are going to be talking about a very compelling editorial that is called “You Get (offered) What You (can) Pay for: Explaining Disparities in End-of-Life Cancer Care." And this was published on June 20th, 2023, in the Journal of Clinical Oncology as an editorial on an article entitled the "End-of-Life Systemic Oncologic Treatment in the Immunotherapy Era: The Role of Race, Insurance, and Practice Setting." So a very timely topic and very exciting for us to discuss today. I'm joined by two of the authors of the editorial, Dr. Holly Prigerson, Professor of Sociology and Medicine, the Irving Sherwood Wright Professor in Geriatrics Medicine at the Weill Cornell Medical College and the Director of Cornell Center for Research on End-of-Life Care. Welcome, Dr. Prigerson. Dr. Holly Prigerson: Great to be here. Dr. Shannon Westin: And also accompanied by Dr. Alfred Neugut, the Myron M. Studner Professor of Cancer Research and Professor of Medicine and Epidemiology at Columbia University and the former Associate Director for Population Science and Racial Disparities Program for the Herbert Irving Comprehensive Cancer Center at Columbia. Welcome, Dr. Neugut. Dr. Alfred Neugut: Thank you very much. Dr. Shannon Westin: Very excited to talk about this topic today, and I like to always start with a little bit of level setting. So I'd love for one of you to discuss: How common is the use of systemic anticancer treatment at the end of life? Dr. Holly Prigerson: So, based on the article, it looks like the rates within the last 30 days of death, it was 34% on average overall. So that was sort of the—you say level setting—the base statistic. Within 14 days of death, it dropped to 13% overall. So all the associations that are described are really disparities from that level.  Dr. Neugut: Speaking as an oncologist, I don't think any of my clinical colleagues will be surprised that it's that high. There is an effort made really to, in desperation, try to help. Patients want it. Families want it. So there really is efforts made to try to do that to prolong life or palliate or whatever. Dr. Holly Prigerson: The design also, which is probably going to be a question that's coming up, does raise a question for me that I'm wondering if Al could enlighten at least me on. They did select patients who were getting treatment for metastatic or advanced cancer starting in 2011 and then who died four years later. Does the selection for the fact that they were getting treatment initially—because everyone, that's how they sampled the study—does that increase the likelihood that they'll get treatment later on so that the rates are somewhat inflated is my question.   Dr. Alfred Neugut: Yeah, no, for sure. People who start chemo tend to continue partially because there is a certain amount of those who do well do well. If you respond to chemo initially, you tend to respond to the second-line therapy, you tend to respond to third-line therapy. If you didn't do well on first-line chemo, you're not likely to respond to a second line or a third line, so you don't have the enthusiasm to continue with it, and the patient certainly tends to lose interest in it. So you're right; there is a certain, call it, momentum or inertia in going forward with chemo once you've started. Dr. Shannon Westin: I mean, I think this just always highlights some of the issues we have, right, with any kind of retrospective data is how well can we design a population without—because we can't always do randomized control trials, and certainly not in this kind of setting. That would not be acceptable, I think, to providers nor patients. And I do agree that it can be tricky. Any other kind of, maybe just to help the listeners if they haven't gotten a chance to read this Canavan study, about the design, exactly what they were looking at in this population?   Dr. Holly Prigerson: Basically, they took these patients who were getting systemic therapy and had advanced metastatic cancer prior, and then who died. So there's always a question about the sampling on death issue, that they had to have died to be in the sample. So those are methodological issues, but there's really very little way around that. If you want to know what treatments people received in the last month of life, they have to die for there to be a last month of life.  So then the treatments were divided into chemotherapy alone, chemotherapy with immunotherapy, and then immunotherapy with and without targeted therapy. So there were three types of treatment, which is sort of an important update because Al and I had published something in 2015 on chemotherapy and the outcome of what was called palliative chemotherapy at that time. And this was sort of a very refreshing–well, not—I shouldn't say refreshing, but important update to our study, which had said that there are questionable outcomes of palliating someone with palliative chemotherapy so far along in the disease. And then the question became, well, is it different? Is it different with immunotherapies? Is it different with targeted therapies? And that's why I was delighted to see this paper, because it answered…  Dr. Alfred Neugut: I'd have to say there are probably differing views on this, but Holly and I are probably relatively nihilistic in terms of thinking that chemotherapy in late stages or near terminal patients is probably not all that helpful. Third-line, fourth-line therapy probably not going to get you very far. And maybe it's best to be thinking more about hospice care and supportive care. And now we have terrific palliative care programs at most or all cancer centers, and we really should be taking advantage of this. I think a real benchmark study was the Temel study from 2010 or 2011, which really—for those of your listeners who haven't read it or seen it, they should really take a look at it. It really changes the playing field and makes you realize that treatment is not really always the best thing for patients, and there are other options. And we go to hospice care or palliative care really, I think, too late in the game a lot of the time, and we really should be thinking otherwise.  Dr. Holly Prigerson: That is one of the outcomes that we had looked at before. So we had looked at palliative chemo, and not only does it not palliate, and we didn't show that it significantly enhanced survival; we also showed that it resulted in a lower likelihood of earlier enrollment in hospice, a higher likelihood of not dying where your family members thought you would have wanted to die, a higher likelihood of dying in the ICU or getting some kind of aggressive care. So it's not only what the chemo does or doesn't do in terms of treatment or survival or quality of life; it also seems to exacerbate and put someone at risk for very burdensome interventions that having avoided it might have enabled patients to avoid getting very burdensome care that's largely futile. But as Al said, we are probably more the nihilistic type.  Dr. Shannon Westin: Well, I think you bring up a couple of good points because you've got objective data, and these studies that you're mentioning are just some of them that show that early hospice care and early enrollment and even just a palliative care program or a supportive care program or whatever terminology we want to use, people do better, right? They live longer actually from that piece rather than necessarily the more “aggressive measures” of chemotherapy and things. Dr. Holly Prigerson: When there was an extra analysis of the Temel data, I believe they had shown that some of the survival advantage was explained by avoiding toxic chemo. So that's directly relevant. Dr. Alfred Neugut: There is an on the other hand, as always, which is that patients and families often don't want to do that. I mean, they realize that doing that is giving up, so they're reluctant to take hospice care or palliative care as an alternative to another cycle of chemo or another type of chemo. And as you say, you never know; maybe the next one is going to be the winner and there'll be a miracle or there'll be at least some substantial benefit. And then there's always experimental therapy, and now immunotherapy, which is the topic of this article, is the new winner on the block. And it has bright lights around it, and everybody has great hope for it. And it's the new kid on the block, and everyone hopes that that's going to be the big savior.  Dr. Shannon Westin: Right, and I think everyone knows of a story of somebody that was “on death's door” and got immunotherapy or the newest targeted therapy or the newest ADC, so that definitely colors it. And that also colors, I think, the physicians that are offering it, right? Because, yes, I've definitely heard this, and I'm sure you guys have too: nobody should die with such and such cancer without receiving immunotherapy once or without receiving such and such targeted therapy. I hear people say this all the time, and I don't necessarily disagree. It's more that when are we giving it, right? So we should be thoughtful about when we're placing those things. But you're right; there's so many factors that go into these decisions, and it's not cut and dry around what the patients and the family members and the physicians are going to decide. Dr. Holly Prigerson: And I think that Al hits on a really key issue when he used the word “hope” because that seems like what the negotiation appears to be all about. You don't want to disparage someone or not offer them hope if there might… No one wants to say that there isn't hope. No one wants to be the bearer of that kind of bad news. And I guess it leads to—I think that that's part of the driver that ends up providing the gas that drives people to getting more aggressive therapies is because no one wants to be the person to be the wet blanket and disparage hope. And so it might affect how treatments are sold to patients or at least communicated to patients.   There was this one finding in this report that was curious, and it was that patients with undocumented performance status were the ECOG group most likely to get treatment. And so, in terms of what could be done going forward to make people more realistic and not offer hope where it's really, really unlikely, maybe employing more decision rules about requiring the documentation of performance status and ensuring that it's what the ASCO guidelines permit for administering another line of treatment. Because that might be a way to sort of use data to help correct what in psychology we call cognitive distortion, so correct the distortion of this hyper-optimism. It might help correct some of that. We don't want to overcorrect and make people hopeless or depressed, but we want to offer realistic options.  I think that's part of why this paper is so important, and it sort of informs future research to try to unpack some of the findings that they didn't have data on physician characteristics or communication discussions between patients and their oncologists. And maybe that's where the money is. Maybe that's where offering hope in a realistic way or different forms of hope, what to hope for, might be better communicated through more effective communication strategies and ways to enhance patients' abilities to understand what they're agreeing to or not agreeing to.  Dr. Alfred Neugut: And I would add that it's easy for us to sit here and be dispassionate or scientific interlocutors and saying, you know, “It doesn't work, and therefore we're not going to offer it or you shouldn't get it or go on to hospice.” But it's different when you're on the other side of the table. And even us doctors or healthcare professionals or scientists, when you're sitting on the other side of the table and you're the one who's got the cancer or your mother or child, you're not going to be so easily dismissive of getting third-line chemotherapy and having your 5% chance that the tumor will respond to some cocktail of who knows what and you never know. I don't want to say anybody's wrong or that it's stupid. Everybody has to do what they have to do, and we at least have to think about it and know what we're doing and have realistic—at least some idea of the realism of what we're putting people through and the costs and the toxicities and what to expect. Dr. Shannon Westin: I think you guys brought up some really great points, and I do think that there is a huge impact around the communication piece. And we actually just did a podcast on discussion of goals of care at the end of life for adolescents and young adults and how those conversations can be different.  I think the other thing that really caught my eye and, of course, caught your eye when you did the editorial around the Canavan study was this idea that the patients with insurance—with all other things being equal, that the patients with insurance were more likely to receive end-of-life systemic treatment. And it's interesting because typically I feel like we think having insurance and having that support is always a positive thing and has a positive impact on our health, and it most certainly does. So that's not up for grabs. But then this particular study showed that it could potentially have been negative because of all the things that you all just said about the negative impact of care in this 30 days or even 14 days near the end of life. What are the opportunities for intervention at the insurance level? You talked a little bit about provider level and communication. Are there opportunities at the insurance level that we could address? Dr. Holly Prigerson: It does seem like having insurance companies determine what is reasonable and not reasonable to reimburse for. So including things, I would think, like having performance status factored in. What are the criteria for determining whether it's high value care or not? And I'm not an oncologist, so I really am going out on a limb, and I really want Al to respond to that question. But from my perspective, it seems like the ASCO guidelines determine when it's—“low-value care” is how they put. It's wasteful and futile and burdensome. And they have guidelines of performance status, having not responded to multiple lines of chemotherapy, so that there could be guidelines for when there is value and when there isn't and that it could be more values driven in terms of guidelines of what they would reimburse. Because, as our title implicated, it seems like you get offered what insurance companies are willing to pay for, and that leads to potential disparities in equity if you have different insurance than other people and fairness and justice. Those seem like valid questions to raise. Dr. Alfred Neugut: I mean, I think if we're following randomized trials and evidence-based medicine, then I think we're in a reasonable area of what should be done and could be done and needs to be done. And almost always, insurance will follow those. You don't usually end up then having to argue with a peer-to-peer call to the insurance company under those circumstances. Where things get sticky is when you want to treat someone off-label or go off the reservation. I don't know if that's to some degree what this paper talked about. And there you probably don't get much benefit from treatment if it's not a data-driven use of the drug. So that's really, I think, where the line needs to be drawn. I don't think there you'll have an insurance problem if you've stated those sorts of guidelines. If you want to use NCCN or the ASCO guidelines, all good and reasonable. The problem is when someone's desperate and you're trying to make them happy, so you give them something even though there's no reason on God's earth why it should work, but just so they feel like you're getting something and you're not being abandoned, which sometimes you do feel pressured to do that, and very commonly you do. And maybe that's where racial disparities save the uninsured from being tortured for something that's not likely to really be very helpful.  Dr. Holly Prigerson: But as someone who's a disparities researcher as well, it raises the question were Black patients—which these data couldn't answer: were they offered different treatments than the White patients? And I think we all agree that low-value treatments shouldn't be offered or received, but the fact that Black patients receive less of the expensive stuff, the newer cutting edge, is problematic. And I think there does need to be more research into equity in terms of the options presented to patients with similar diagnoses. That was the troubling aspect of it, not that they weren't getting, in essence, better end-of-life cancer care, but that's beside the point. In terms of ethics, it would be nice to have known whether they were offered the same things and declined it. I think all of us are a little suspicious that maybe they weren't.  Dr. Shannon Westin: Yeah, that definitely—I like how you said it. It struck a nerve. Like, when I was reading through both the article and your editorial, that was something that caught my eye is this evidence of how implicit bias is impacting what people are offered. And yes, it ended up being an overall benefit to underrepresented minority patients. However, that wasn't necessarily the intention or why that happened. So I would be interested to hear what you all think about what we know about how implicit bias impacts the care of patients with cancer, just for our listeners, and specifically what particular treatments are offered, not necessarily just at the end of life, but just across the cancer continuum.  Dr. Alfred Neugut: There are estimates—if you read the medical literature on health policy and things like that, there are estimates that we overdo a lot of things in medicine and give—I don't know. I've read that like 70% of what we do in medicine is unnecessary. I'm not saying in oncology necessarily, but screening and wellness care, etc. And so oncology probably is equally guilty of such things. And there are biases in that as well, so, you know, that's what happens.   Dr. Holly Prigerson: And in the article, they had cited, I think it's Penner. There was a study that showed that ratings of an oncologist's implicit bias were negatively associated with Black patients' willingness to undergo their treatment recommendations. So the dynamic between what's offered, what's heard, what's trusted. There's obvious history of Tuskegee and concerns about being denied treatment. So this article kind of feeds into why was the latest and greatest types of treatment not as common? That said, the actual differences, if you look in the tables, the actual differences weren't that disparate. They were statistically significant, but we're talking like 37% to 34%. So the disparity isn't as wide as to cause serious alarm bells to go off that people are being treated so differently. But it does raise a lot of underlying concerns that you would want to make sure that everyone's being offered the same things. So it does imply—that Penner article implied—it's basically medical mistrust may be interfering with a Black patient's willingness to undergo or accept some treatment offered. So if you follow the logic on that through, then the intervention would be: What are ways to enhance medical mistrust of their oncologist? What are the reasons for it? And how can patients feel that they are being treated by someone who treats them fairly and no differently than White patients? And so efforts in those directions seem like they might pay off in terms of enhancing and addressing implicit bias.  Dr. Shannon Westin: Well, this has been a really great discussion. I'd love to hear just kind of your last thoughts from each of you around some of the unmet needs. We've heard themes throughout the discussion, but maybe just sum it up for the podcast listeners, bring them back and where we need to go next here.  Dr. Holly Prigerson: Al and I have been working on a few different projects to address medical mistrust and leveraging things like healthcare chaplains, who might be liaisons within an outpatient oncology setting. We also have interventions that try to enhance clinical communication, like what we call a GIST, so that patients easily get the gist, the essential meaning of things like scan results to sort of level the playing field so that patients have adequate information to know what the harms and benefits of the treatments that they're being offered might be and have a better background to be engaged in those decisions in the first place.  Dr. Alfred Neugut: My own thing is that you should be telling patients right from the get-go that they have incurable diseases and not letting them meander along thinking that we can actually help cure them in some meaningful way. We know who's incurable, and even if they have two or three years of survival coming to them, colorectal cancer or breast and prostate, etc., it's still fair to tell them that we can't cure them. And then when the time does come two, three, four years later, they're not going to be shocked, and they'll deal with it, I think, in a better way because they've known all along that this day is going to come, and then they don't react badly in the last two weeks, three weeks, four weeks, because they've been prepared for all those years before. I think the real problem is no one ever tells them directly, or many doctors don't tell them directly upfront. And so, when it comes near the end, they don't tell them until they're almost semiconscious. Then it's a shock out of the blue. And then of course they want to be treated more aggressively at the end. And I think that's where some of the issues may come. Dr. Holly Prigerson: And with the immunotherapies, that probably raises a lot more questions, even from the oncologist's perspective, about what they can call incurable because maybe there is hope, maybe there are these outliers. That's where it seems like it's wonderful that there are advances, but if the rates are so low and people have a misunderstanding of their chances, I think we're on the side of understanding what the best data suggests are the likely outcomes. And I think all the new advances sort of undermine disparaging hope because that's what they're there to do. They're there to offer hope. Dr. Shannon Westin: And everybody wants to be the tail of the curve, right? They all want to be that person. So that's exactly—you're totally right. When we're trying to communicate, “Okay, this is the most common outcome.  Yes, there are people that are way over here but…”  Dr. Holly Prigerson: That's going to be me. Dr. Shannon Westin: Yes. They always say, “That's going to be my miracle.” Well, great. Well, thank you both so much. This was such a lively discussion, and I know the listeners learned a ton. I know I did.  Again, thank you all for listening to JCO After Hours. We were discussing "You Get (offered) What You (can) Pay For: Explaining Disparities in End-of-Life Cancer Care," published in the JCO 6/20/23. We're so excited that you took the time to listen. If you're looking for more podcasts, check out our website, or you can find us 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.  

Vor nicht allzu langer Zeit waren Sebastian Henßler von Elektroauto-News.net und BnB Host York Kolb auf der BayWa Charging Night unterwegs, die am Vorabend der Münchener Messe Power2Drive stattgefunden hat. Und genau auf solchen Events trifft man bekanntlich jede Menge spannender Menschen aus der E-Mobilitäts-Szene. So ist York z. B. mit Mirjam Laubenbacher, Head of Communications des Scale-ups EcoG, ins Gespräch gekommen. Das war so interessant, dass wir direkt einen Termin für eine Podcast-Aufnahme mit ihrem Kollegen und CTO Dr. Johannes Hund vereinbart haben. EcoG ist gewissermaßen eine Ausgründung aus dem Siemens-Konzern und schon heute in Europa, Nordamerika sowie Indien aktiv. Auf ihrer Webseite ist der folgende, imposante Satz zu lesen: „EcoG ist für mehr als 15 % der DC-Charger in Europa verantwortlich, wir können unsere Lösungen überallhin liefern und die lokalen Standards erfüllen.“ Doch was macht das Unternehmen eigentlich konkret? Das erzählt euch Johannes in dieser Folge persönlich. Viel Spaß beim Reinhören und gute Unterhaltung! --- WERBUNG: Der BYTES ,N' BATTERIES Podcast wird unterstützt von Hankook und iON, der globalen Reifen-Familie speziell für Elektroautos --- Special thanks to / Unser besonderer Dank gilt: Johannes Hund & Mirjam Laubenbacher, EcoG ---- Unterstützer: Hankook Tire https://www.hankooktire.com/de/de/home.html Pressemitteilung iON Reifen-Familie ---- Feedback und Anfragen: agentur@brands-in-green.com https://bytesnbatteries.de/ Instagram: @bytesnbatteries_podcast

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.28.551050v1?rss=1 Authors: Ryu, J., Choi, J.-W., Niketeghad, S., Torres, E. B., Pouratian, N. Abstract: Background: Goal-directed movements involve integrating proprioceptive and visuo-motor information. Although the neural correlates of such information processing are known, the details of how sensory-motor integration occurs are still largely unknown. Objective: The study aims to characterize movements with different sensory goals, by contrasting the neural activity involved in processing proprioceptive and visuo-motor information. To accomplish this, we have developed a new methodology that utilizes the irregularity of the instantaneous gamma frequency parameter for characterization. Approach: In this study, 8 essential tremor patients undergoing an awake deep brain stimulation (DBS) implantation surgery repetitively touched the clinician's finger (forward visually-guided/FV movement) and then one's own chin (backward proprioceptively-guided/BP movement). Neural electrocorticographic (ECoG) recordings from the motor (M1), somatosensory (S1), and posterior parietal cortex (PPC) were obtained and band-pass filtered in the gamma range (30-80Hz). The irregularity of the inter-event intervals (IEI; inverse of instantaneous gamma frequency) were examined as: 1) correlation between the amplitude and its proceeding IEI, and 2) auto-information of the IEI time series. We further explored the network connectivity after segmenting the FV and BP movements by periods of accelerating and decelerating forces, and applying the IEI parameter to transfer entropy methods. Results: Conceptualizing that the irregularity in IEI reflects active new information processing, we found the highest irregularity in M1 during BP movement, highest in PPC during FV movement, and the lowest during rest at all sites. Also, connectivity was the strongest from S1 to M1 and from S1 to PPC during FV movement with accelerating force and weakest during rest. Significance: We introduce a novel methodology that utilize the instantaneous gamma frequency (i.e., IEI) parameter in characterizing goal-oriented movements with different sensory goals, and demonstrate its use to inform the directional connectivity within the motor cortical network. This method successfully characterizes different movement types, while providing interpretations to the sensory-motor integration processes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.26.550669v1?rss=1 Authors: Idesis, S., Geli, S., Faskowitz, J., Vohryzek, J., Sanz Perl, Y., Pieper, F., Galindo-Leon, E., Engel, A. K., Deco, G. Abstract: Brain signal irreversibility has been shown to be a promising approach to study neural dynamics. Nevertheless, the relation with cortical hierarchy and the influence of different electrophysiological features is not completely understood. In this study, we recorded local field potentials (LFPs) during spontaneous behavior, including awake and sleep periods, using custom micro-electrocorticographic (ECoG) arrays implanted in ferrets. In contrast to humans, ferrets remain less time in each state across the sleep-wake cycle. We deployed a diverse set of metrics in order to measure the levels of complexity of the different behavioral states. In particular, brain irreversibility, which allows us to quantify the level of non-equilibrium captured by the arrow of time of the signal, revealed the hierarchical organization of the ferret's cortex. We found different signatures of irreversibility and functional hierarchy of large-scale dynamics in three different brain states (active awake, quiet awake, and deep sleep), showing a lower level of irreversibility in the deep sleep stage, compared to the other. Irreversibility also allowed us to disentangle the influence of different brain regions and frequency bands in this process, showing a predominance of the parietal area and the theta band. Furthermore, when inspecting the embedded dynamic through a Hidden Markov Model, the deep sleep stage was revealed to have a lower switching rate and lower entropy production. These results suggest functional hierarchies in organization that can be revealed through thermodynamic features and information theory metrics. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

El Dr. Luis Alfonso Romero, oncólogo médico de León, Guanajuato, México, en este episodio de “Pase de visita” abordará un caso clínico de una paciente con diagnóstico de adenocarcinoma de páncreas. Como invitados al programa se encuentran tres médicos mexicanos, el Dr. Manuel Aguilera, oncólogo médico adscrito al Centro Médico Nacional “Siglo XXI” en la Ciudad de México; el Dr. Eduardo Valtierra, cirujano oncólogo adscrito a la UMAE León del IMSS en Guanajuato, y el Dr. Jordi Guzmán, oncólogo médico adscrito al Hospital San José Moscati en Querétaro. Ellos, con base en evidencia científica y en su experiencia, responderán a varias interrogantes. El caso clínico trata de una mujer de 57 años, mínimamente sintomática y con ECOG 1, a la cual, por síntomas de reflujo crónico, se le hace un ultrasonido y una tomografía abdominal en donde se observó un tumor en el cuerpo del páncreas de 4 cm con reforzamiento al medio de contraste adyacente a tronco celiaco (sin infiltrarlo ni cubrirlo más del 30%). Se procedió con realizarle un ultrasonido trasendoscópico con toma de biopsia, reportando un adenocarcinoma de páncreas moderadamente diferenciado e invasor sin presencia de ganglios linfáticos peripancreáticos, por lo que las preguntas para los médicos sobre este caso son las siguientes: ¿Se le podría ofrecer tratamiento sistémico neoadyuvante a esta paciente? En caso de ser canditada a la neoadyuvancia, ¿cuál sería el esquema preferido de tratamiento? ¿Se considera preferible la cirugía de inicio o se plantearía primero tratamiento neoadyuvante para mejorar las opciones quirúrgicas? En pacientes con cáncer de páncreas, ¿existe un incremento en riesgos perioperatorios en aquellos que reciben un tratamiento preoperatorio?   Fecha de grabación: 11 de julio de 2023.                   Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In this episode of ASCO Educational podcasts, we'll explore how we interpret and integrate recently reported clinical research into practice. Part One involved a 72-year old man with high-risk, localized prostate cancer progressing to hormone-sensitive metastatic disease. Today's scenario focuses on de novo metastatic prostate cancer. Our guests are Dr. Kriti Mittal (UMass Chan Medical School) and Dr. Jorge Garcia (Case Western Reserve University School of Medicine). Together they present the patient scenario (1:13), going beyond the one-size-fits-all approach (4:54), and thinking about the patient as a whole (13:39). Speaker Disclosures Dr. Kriti Mittal:  Honoraria – IntrinsiQ; Targeted Oncology; Medpage; Aptitude Health; Cardinal Health  Consulting or Advisory Role – Bayer; Aveo; Dendreon; Myovant; Fletcher; Curio Science; AVEO; Janssen; Dedham Group  Research Funding - Pfizer Dr. Jorge Garcia:  Honoraria - MJH Associates: Aptitude Health; Janssen Consulting or Advisor – Eisai; Targeted Oncology Research Funding – Merck; Pfizer; Orion Pharma GmbH; Janssen Oncology;  Genentech/Roche; Lilly  Other Relationship - FDA Resources  ASCO Article: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019 ASCO Course: How Do I Integrate Metastasis-directed Therapy in Patients with Oligometastatic Prostate Cancer? (Free to Full and Allied ASCO Members) If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Disclosures for this podcast are listed on the podcast page.  Dr. Kriti Mittal: Hello and welcome to this episode of the ASCO Education Podcast. Today, we'll explore how we interpret and integrate recently reported clinical research into practice. In a previous episode, we explored the clinical scenario of localized prostate cancer progressing to metastatic hormone-sensitive disease. Today, our focus will be on de novo metastatic prostate cancer. My name is Kriti Mittal and I am the Medical Director of GU Oncology at the University of Massachusetts. I am delighted to co-host today's discussion with my colleague, Dr. Jorge Garcia.  Dr. Garcia is a Professor of Medicine and Urology at Case Western Reserve University School of Medicine. He is also the George and Edith Richmond Distinguished Scientist Chair and the current Chair of the Solid Tumor Oncology Division at University Hospitals Seidman Cancer Center.  Here are the details of the patient case we will be exploring: The patient also notes intermittent difficulty in emptying his bladder with poor stream for the last six months. A CT scan of the abdomen and pelvis demonstrates enlarged prostate gland with bladder distension, pathologically enlarged internal and external iliac lymph nodes, and multiple osteolytic lesions in the lumbar sacral, spine, and pelvic bones. A CT chest also reveals supraclavicular lymphadenopathy and sclerotic foci in three ribs. So this patient meets the criteria for high-volume disease and also has axial and appendicular lesions.  The patient was admitted for further evaluation. A bone scan confirmed uptake in multiple areas identified on the CT, and a PSA was found to be greater than 1500. Biopsy of a pelvic lymph node confirmed the diagnosis of prostate cancer. This patient is somewhat different from the first case we presented in terms of timing of presentation; this patient presents with de novo metastatic high-volume disease, in contrast to the first patient who then became metastatic after undergoing treatment for high-risk localized disease.  Would you consider these two cases different for the purposes of dosing docetaxel therapy when you offer upfront triplet therapy combinations?  Dr. Jorge Garcia: That's a great question. I actually do not. The natural history of someone with localized disease receiving local definitive therapy progressing over time is different than someone walking in with de novo metastatic disease. But now, with the challenges that we have seen with prostate cancer screening, maybe even COVID, to be honest with you, in North America, with the late care and access to testing, we do see quite a bit of patients actually walking in the office with de novo metastatic disease. So, to me, what defines the need for this patient to get chemotherapy is the volume of his disease, the symptoms of his disease – to be honest with you – and the fact that, number one, he is clinically impaired. He has symptomatic disease, and he does have a fair amount of disease, even though he may not have visceral metastasis. Then his diseases give him significant pain.  Oral agents are very good for pain control. I'm not disputing the fact that that is something that actually these agents can do. But I also believe I'm senior enough and old enough to remember that chemotherapy, when it works, can actually really alleviate pain quite drastically. So for me, I think that the way that I would probably counsel this patient is to say, "Listen, we can give you ADT plus an oral agent, but I really believe your symptomatic progression really talks about the importance of rapid control of your disease.” And based upon the charted data from the United States, and equally important, PEACE-1, which is the French version of ADT, followed by abiraterone, if you will, and certainly ARASENS is the standard of care for me for a patient like this will be triple therapy with ADT and docetaxel.  What I think is important for us to remember is that, in ARASENS, it was triple therapy together. I am worried sometimes about the fatigue that patients can have during the first six cycles of docetaxel. So oftentimes, I tell them if they're super fit, I may just do triple therapy up front, but if they I think they're going to struggle, what I tell them is, "Hey, we're going to put you on ADT chemotherapy. Right after you're about to complete chemo, we'll actually add on the darolutamide." So I do it in a sequence, and I think that's part of the data; we just still don't know if it should be given three at front or ADT chemo, followed by immediately, followed by an ARI. So I love to hear if that's how you practice or you perhaps have a different thought process. Dr. Kriti Mittal: So I usually start the process of prior authorization for darolutamide the day I meet them for the first time. I think getting access to giving docetaxel at the infusion center is usually much faster than the few weeks it takes for the prior authorization team to get copay assistance for darolutamide. So, in general, most of my patients start that darolutamide either with cycle two or, depending on their frailty, I do tend to start a few cycles in like you suggested. I've had a few patients that I've used the layered-in approach, completing six cycles of chemotherapy first and then layering in with darolutamide.  I think conceptually the role of intensifying treatment with an androgen receptor inhibitor is not just to get a response. We know ADT will get us a PSA response. I think the role of an androgen receptor inhibitor is to prevent the development of resistance. So, delaying the development of resistance will be pertinent to whether we started with cycle one, cycle six, or after. So, we really have to make decisions looking at the patient in front of us, looking at their ECOG performance status, their comorbidities, and frailty, and we cannot use a one-size-fits-all approach.  Dr. Jorge Garcia: Yeah, I like that and I concur with that. Thank you for that discussion. I think that you may recall some of our discussions in different venues. When I counsel patients, I tell the patients that really the goal of their care is on the concept of the three Ps, P as in Peter. The first P is we want to prolong your life. That's the hallmark of this regimen, the hallmark of the data that we have. That's the goal, the primary goal of these three indications is survival improvement. So we want to prolong your life so you don't die anytime soon from prostate cancer.  The second P, as in Peter, is to prevent, and the question is preventing what? We want to prevent your cancer from growing, from growing clinically, from growing radiographically, and from growing serologically, which is PSA and blood work. Now, you and I know and the audience probably realize that the natural history of prostate cancer is such that traditionally your PSA will rise first. There is a lead time bias between the rise and the scan changes and another gap in time between scans and symptoms. So it's often not the case when we see symptomatic disease preceding scans or PSAs, but sometimes in this case, it's at the same time. So that is the number one. And as you indicated, it's prevention of resistance as well, which obviously we can delay rPFS, which is a composite endpoint of radiographic progression, symptomatic progression, and death of any cause.  But the third P is I called it the P and M, which is protecting and maintaining, and that is we want to protect your quality of life while we treat you. And we want to maintain your quality of life while we treat you. So to me, it's critically important that in addition of aiming for an efficacy endpoint, we don't lose sight of the importance of quality of life and the protection of that patient in front of us. Because, undoubtedly, where you get chemo or where you get an oral agent, anything that we offer our patients has the potential of causing harm. And I think it is a balance between that benefit and side effect profile that is so critically important for us to elucidate and review with the patient.  And as you know, with the charted data, Dr. Alicia Morgans now at Dana-Farber, published a very elegant paper in JCO looking at the impact of docetaxel-based chemotherapy as part of the charted data in the North American trial and into quality of life. And we clearly define that your quality of life may go down a bit in the first few months of therapy, predictably because you're getting chemotherapy. But at the end of the six months, nine months, and certainly at the end of a year mark, the quality of life data for those who receive ADT and chemotherapy was far better than those who actually got ADT alone.  Now, if you look at the quality of data for RSNs, a similar pattern will appear that although chemotherapy is tied to misconceptions of significant toxicity, in our hands, in good hands, and I think our community of oncology in North America are pretty familiar with the side effects and how to manage and minimize side effects on chemotherapy, I think it still requires a balance and a thoughtful discussion to make sure that we're not moving forward chasing a PSA reduction at the expense of the quality of life of the patient. So I think orchestrating that together with the patient as a team is critically important as well.  Dr. Kriti Mittal: Thank you, Dr. Garcia. Moving on to the next concept we'd like to discuss in today's podcast the role of PARP inhibitors. Case Two was treated with androgen deprivation docetaxel and darolutamide. Consistent with current guidelines, the patient was also referred to germline testing and was found to be BRCA 2-positive. The patient's disease remained stable for 24 months, at which time he demonstrated disease progression, radiographically and clinically, and his disease was termed castration-resistant. There has been a lot published in the last few years regarding the role of PARP inhibitors in metastatic castration-resistant prostate cancer, or mCRPC.  The PROfound trial led to the approval of olaparib in patients with deleterious mutations in HRR genes for those who had been treated previously with AR-directed therapy. The TRITON2 trial led to the approval of rucaparib in the same month for mCRPC patients with BRCA mutation for those patients who had previously been treated with AR inhibitors and taxine-based chemotherapy. More recently, we saw data from the TRITON3 trial exploring the role of rucaparib versus physicians' choice of docetaxel versus AR-inhibitor therapy in the mCRPC space for patients harboring BRCA 1, BRCA 2, or ATM mutation. Based on these data, it would be very tempting to offer a PARP inhibitor to the patient in case two. While regulatory authorities are still reviewing those data for approval, how would you consider treating this newly castrate-resistant patient in the frontline setting? Would you consider a PARP inhibitor in the frontline treatment of mCRPC in this patient with a BRCA 2 mutation? Dr. Jorge Garcia: So that's a loaded question, to be honest with you. We have compelling data, but controversial data, as you know as well. So I think that since we have a genomic profile on this patient and we know he had high volume disease, then the first thought to me is not a genetic or a genomic question or a sequence. It's actually a clinical question, to be honest with you. And that is: How are you progressing? Because I think that if you're progressing serologically, you and I may think of that patient differently. If you're progressing radiographically with alone plus minus PSA production but no symptoms, you may also tilt your scale into this life-prolonging agents in a different way. Whereas if you have true symptomatic disease, knowing what you know, prior therapy, CrPC with a BRCA 2 alteration, then you may actually go for something different.   So if it's a rising PSA, if it is radiographic, but the patient is stable clinically, is not basically compromised by symptomatic disease, I do feel that a PARP inhibitor as a single agent would be a very reasonable choice. In this case, you can use, obviously, rucaparib. You can use olaparib. I don't have a vested interest in either/or. I think either/or is fine. The subtleties and side effects, as you know, the olaparib data was probably the data that you and I probably are more accustomed to, used to the most just by virtue of how the agents got registered in the United States. But either/or, I think a PARP inhibitor would be a reasonable approach.   I think the question perhaps, and I pitch that back to you, is what are you looking for with a PARP inhibitor? Because, as you know, all DNA repair deficiencies are not biologically the same. They do not respond the same way to PARP inhibitors. And even BRCA 2, where we think it's monoallelic or biallelic, may have subtleties in how those patients respond to PARP therapy. But the answer is yes, obviously, you have a biomarker, the patient has it, you can use it. I think the question is, how are you going to follow the patient? And what is going to be the endpoint that you're going to pay attention to in this case to find that the patient has a benefit or not granted, that could be PSA driven, but I think that perhaps I'm pushing you to think beyond PSA.  Dr. Kriti Mittal: I agree, Dr. Garcia. I think we need to think about the patient as a whole. PSA-based changes in treatment are not generally part of our practice. I think evaluating the patient for symptoms and also thinking about the sites of progression, sites of disease they've had in the past, preventing development of cord compression, because some of these patients progress very rapidly and present with cord compression at the time of progression. Those are the things we are trying to predict and prevent. I think in a patient with BRCA 2 mutation, in this situation, I would feel compelled to offer rucaparib, given that even in the intention-to-treat analysis, the hazard ratio was 0.6 in terms of median progression-free survival. I think what was quite impressive was the subset analysis comparing rucaparib versus docetaxel. And that was something surprising. And I think we'll have to wait for long-term outcomes. But certainly, for a BRACA 2-mutated patient, this could be a reasonable consideration provided the drug is available and approved.  Dr. Jorge Garcia: As you know, the three most common DNA repair deficiencies that we see are BRCA1, BRCA2, and ATM. BRCA2 is probably the one that we see the most. But we also recognize that with the limited data we have for ATMs, that patients with an ATM abnormality do not tend to benefit the most. And then yet we have also another series of DNA repair deficiencies, deficiencies, PALB2, CHEK2, CDK12 and so forth. And yet we have some exquisite responses to some of those patients.   So I can tell you that I have a patient of mine who had an ATM mutation, a germline ATM mutation, and I predicted that initially that the likelihood of benefit to a PARP inhibitor would be low. He was placed on a PARP inhibitor and surprise, surprise, he was on a PARP inhibitor for almost a couple of years. What I want to convey to the audience is that if you have the appropriate biomarker, you certainly should consider a PARP inhibitor in this scenario.   I think the bigger question is also understanding that not every DNA repair would benefit the same way. So being very thoughtful and very structured as to how you're going to manage the patient, it cannot be PSA only, the patient has to be followed radiographically and clinically because I would argue that if this patient had just a serologic progression, I would put the patient on a PARP inhibitor and the PSA kinetics change north, but slowly, what is the urgency of you switching the patient to something else?   And also the misconception that if you look at PROfound, that olaparib for that matter has to always be given after docetaxel. That's not the case. The makeup of PROfound is different than this patient, obviously, because this patient got triple therapy upfront, whereas most patients on the PROfound were CRPC who receive chemotherapy in the CRPC space. But yet undoubtedly, I think that your case illustrates the importance of next-generation sequencing and the importance of understanding the access to two oral PARP inhibitors that are super solid.  I think that perhaps the bigger question is going to be should you do a PARP inhibitor alone or should we use a combination of a PARP inhibitor plus an oral agent, such as in this case, maybe abiraterone acetate plus olaparib. Or maybe even thinking of TALAPRO, maybe enza plus a PARP inhibitor. So I don't know where you sit on those thoughts, Doctor-. Dr. Kriti Mittal: I change toxicity considerations, temper my enthusiasm for offering PARP inhibitors in combination with AR inhibitors or abiraterone at this time. I think I would certainly consider monotherapy with rucaparib for a patient in this situation. I am not entirely convinced that putting a patient through dual treatment in the mCRPC setting in the frontline, I don't think we are there yet. Dr. Jorge Garcia: There are two very important trials that are looking at the combination of an adrenal biosynthesis inhibitor plus olaparib in this context, and one is PROpel and the other one is MAGNITUDE. And both trials have very different results in many ways because they look at patients with a biomarker, meaning DNA repair, and patients without the biomarker. And I think the bigger question is, should this patient who was an abiraterone– Let's say this patient hypothetically was on a PEACE-1-like style. So the patient got ADT or triple therapy but was an abiraterone or an adrenal biosynthesis inhibitor instead of chemotherapy. And the patient was progressing slowly on abiraterone, you knew that the patient had a DNA repair deficiency. How comfortable with the PROpel and MAGNITUDE data would you and I feel to add on or layer, if you allow me to express it like that, a PARP inhibitor into this regime? Dr. Kriti Mittal: My personal interpretation of the currently available data is that at this point, combination therapy is not something I would use in my clinical practice. I think there are two camps in the GU oncology community of how people interpret the PROpel, MAGNITUDE, TRITON, and TALAPRO data in full. I think each of these trials had very different patient populations. I think in a biomarker unselected population, I would certainly not advocate for combination therapy. But even in the biomarker-selected population, I think how the biomarkers were tested and how the populations were defined may not always match what we are doing in clinical practice. And so I would, at this time, advocate for monotherapy over combination therapy. Dr. Jorge Garcia: I'm sure the audience will have probably read or heard about PROpel and MAGNITUDE and the data in patients without a biomarker positivity disease. So I'd love to hear your thoughts as to if you had no biomarker. By that I mean if you had a patient with CRPC, with metastatic CRPC without a DNA repair deficiency, would you consider using an adrenal biosynthesis inhibitor and a PARP inhibitor together based upon the potential synergistic of additive benefits and some of the data to suggest that you can delay rPFS when you combine therapy, but in the absence of biomarker positivity. Dr. Kriti Mittal: In the absence of biomarker positivity, I think the preclinical data are stronger than the clinical results we are seeing in trials. So while I think we should continue researching further into this because there certainly is preclinical rationale, looking at the clinical outcomes from these several trials, I would not offer PARP inhibitor to an unselected patient. Dr. Jorge Garcia: Great. Dr. Kriti Mittal: Moving on to second-line treatment for castration-resistant prostate cancer. I think talking of access issues and talking about the current treatment paradigms in the United States, there is still not widespread availability of lutetium. The listeners would love to hear your thoughts, Dr. Garcia, on practical management tips, safety issues, and the multidisciplinary nature of the management of lutetium therapy.  Dr. Kriti Mittal: So I think the challenges with lutetium are multiple. Number one is the correct identification of the patient, the ideal patient for lutetium. Secondly is who manages the patient and as you indicated, the importance of a team approach in that. Thirdly is how do we follow that patient during therapy? So it's beyond the technical aspects of who infuses the patient. Fourthly is what are the true goals of lutetium for that patient population and the side effects that those patients may embark on that some people may not be fully aware of and creates complexity. And lastly, perhaps, is how the movement, how we develop lutetium in CRPC and how we're going to move lutetium or have started to move lutetium and alike, meaning radiopharmaceuticals, radioligand-based therapies outside lutetium opinion and others as you know, earlier into the natural history of prostate cancer, maybe even in the locally advanced disease in combination with radiation or for patients with N1 positive disease. So it's a lot of movement in that space. I think that this is just the beginning of radiopharmaceutical entering diagnostics. But let me just address this succinctly, if I may. Number one, you do need a PET PSMA in order for you to select the patient because we're talking about a potential biomarker. But this is what I call an imaging biomarker. If you see it, you treat it.  So the standard of care right now for lutetium is very simple: you need to have men with metastatic castration-resistant prostate cancer. Two, you need to have failed a prior oral agent, in this case, a novel hormonal agent, independent of which agent you have seen, independent of the timing when you have seen an oral agent at the front, the middle, the end. And lastly, you have to have progress through chemotherapy. Yet again, it depends on when you see chemo.  So if you have someone who has high volume metastatic disease from the beginning, de novo disease, and you got ADT, daro, and docetaxel, and the patient progresses, that patient can go on. If that patient has a positive PSMA PET, that patient can go on to get lutetium. Similarly, if you have someone who got ADT alone in the adjuvant space for radiation therapy, progress, got an oral agent, progress, got a PARP or not, or got docetaxel, that patient could also be a candidate for lutetium. It's dependent on how you run the patient through therapy.  Secondly is who gives lutetium? So I do believe, and I may be biased, I certainly believe in the importance of a team approach with radiation oncology and nuclear medicine. But the reality of it is, I believe these patients are so advanced in their stage of their disease, then the idea of quarterback, in my personal opinion, resides in medical oncology. And I think the bigger question is going to be if nuclear medicine at your given institution is going to be delivering lutetium, or is it going to be radiation oncology? And I think, as you know, in places in America, it's RadOnC, in other places is NucMed, in our institution right now it is NucMed. Having said that, I do predict that for those places where nuclear medicine is heavily involved in delivering lutetium or partnering with MedOnc to deliver lutetium, radiation oncology in the future will have a bigger role as well because we are moving lutetium earlier in settings where radiation oncology is commonly used, such as high-risk prostate cancer patients, or even in the salvage setting, or even in patients with metastatic disease, where we want to combine radiation and lutetium, which are part of clinical trials as we think through for the future. But either/or, I think the quarterback should be really MedOnc in this case.  Thirdly is how do we do it? So clearly, at least in my practice, and I think it's probably standard across the United States, MedOnc will see the patient, determine viability and feasibility of therapy, determine who's the ideal candidate, discusses the pros and the cons, and then works along with RadOnc or NucMed to start the process. As you know, it is once every six weeks. So here in my practice, we will see the patient every time before treatment. Sometimes we see them the day off, sometimes we see them a few days before. Patients will get blood work. Specifically, we're interested in seeing everything CMPs, but certainly blood counts, red cell counts, platelets, and white cell counts, just to make sure that patients do not start with impaired bone marrow that can increase the risk for myelosuppression and therefore significant challenges with side effects, hematologic side effects, specifically. And we do that.   Sometimes we see them, sometimes our nurse practitioners would do so. And then the patient will basically follow through and complete up to six cycles of treatments. Six times six, that's actually 36 weeks or so. That's a long time on therapy for those who can get six cycles. I think the question becomes how do you follow those patients? And if we pay attention to the VISION data, as you know, those patients were actually followed serially quite closely on trial every eight weeks for the first 24 weeks, and then they stretch the scans out. But the scans that we're using in the trial are conventional imaging.  And I think the bigger question that you and I will have is if we get a PET PSMA to use to make that decision to get on lutetium PSMA, should I go back and use a CT or so to stage the patient? I think we're moving more toward PET follow-up, but we also don't know fully the impact of lutetium PSMA on PSMA metabolically during treatment. I think that we all recognize anecdotally and at least with some of the emerging data and we have the SUV may change, that PSA reductions also appear to be important as to define who is likely to benefit or not. But those are questions that remain to be seen, to be honest with you. We follow the patients serologically, clinically, and radiographically. And at least in my group, we tend to do PSMA PETs in between therapy to ascertain the impact of therapy in radiographic and also metabolic changes. And lastly is how we manage side effects. So I think that I'm pretty OCD about these patients because I have seen in my practice patients having outstanding responses to therapy but unfortunately become transfusion dependent, either transiently or permanently, just by virtue of side effects. And I think the importance of understanding the most common side effects of lutetium, in this case fatigue, myelosuppression, xerostomia, are really, really important. And that is the importance of having a multi-team effort approach so everybody is fully aware of the baseline characteristics of that patient or how the patient is enduring therapy and how the therapy is impacting the quality of life and impacting bone marrow production for those patients.  I think I remind the audience that the vast majority of our patients do have bone metastases. In fact, in the VISION trial it was around what, over 85, 90% of patients are so with bone metastases. So their marrow has already been impacted not only by disease but equally importantly by the prior chemotherapy that they may have seen. And some of the patients that we have in the first bubble effect is they have seen probably docetaxel, some may even have seen dual therapy with cabazitaxel as a second-line chemotherapy. So I think the understanding as to how you manage the side effects is critically important for our patients as well.  Dr. Kriti Mittal: Those are very relevant, practical life issues. Thank you Dr. Garcia for a terrific discussion on the application of recent advances in prostate cancer to clinical practice. [28:54] The ASCO Education podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. Dr. Jorge Garcia: Thank you, Kriti. It's great to see you and thanks again to ASCO for the amazing opportunity to be here with you guys today. I hope the audience can see the benefit of understanding how the many changes we have seen have impacted our patients in a positive way. So thank you again for the opportunity. Dr. Kriti Mittal: Thank you, Dr. Garcia, and thank you so much to the ASCO team for inviting me. This was a great experience.  Thank you Dr. Garcia for sharing your perspective on incorporating recent research advances into the management of patients with de novo metastatic prostate cancer. The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Navneet Singh highlights the latest evidence-based recommendation updates from the ASCO living guideline on stage IV non-small cell lung cancer with driver alterations. This update focuses on new second-line options for patients with advanced NSCLC and an EGFR exon 20 insertion, including amivantamab and mobocertinib. Dr. Singh also discusses updated results from CodeBreaK 200 and the option of second-line therapy with sotorasib for patients with advanced NSCLC and a KRAS-G12C mutation. Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.2” and view all recommendations at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01055  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.   My name is Brittany Harvey, and today I am joined by Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2023.2.” Thank you for being here, Dr. Singh.  Dr. Navneet Singh: Thank you for having me, Brittany. Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the Guideline panel, including Dr. Singh, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into this living clinical practice guideline, Dr. Singh, this living guideline for systemic therapy for stage IV non-small cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations in this version? Dr. Navneet Singh: So for this 2023 version 2 update, three trials were included. These include two studies which involved patients with exon 20 insertion mutations, who had received prior platinum-based chemotherapy and subsequently were treated with either amivantamab in the CHRYSALIS trial or with mobocertinib in the EXCLAIM trial. The third trial which formed the basis for this update was one which involved patients with KRAS G12C mutation who had previously received systemic therapy and subsequently were treated with sotorasib. And this was the CodeBreaK 200 trial. Brittany Harvey: Understood. So then, based on these three new trials that you've just mentioned, what are the updated recommendations from the expert panel for patients with advanced non-small cell lung cancer? Dr. Navneet Singh: For patients with advanced NSCLC with an EGFR exon 20 insertion mutation and an ECOG performance status of 0 to 2 who have received prior platinum-based chemotherapy, clinicians may offer amivantamab or mobocertinib as monotherapy. It is important to mention here that in the absence of head-to-head comparison of amivantamab or mobocertinib with each other or with other standard second-line therapies, no recommendation for sequencing can be made and therefore treatment should be individualized. Now, use of either of the two drugs is based on low-quality evidence and has a weak strength of recommendation. And the updates for treating KRAS G12C-mutated NSCLC is largely similar; that patients who have received prior systemic therapy may be offered sotorasib.  Brittany Harvey: Thank you for reviewing those updated recommendations. So what should clinicians know as they implement these new recommendations and how do they interface with the existing recommendations? Dr. Navneet Singh: It is important for clinicians involved in the management of EGFR mutant lung cancer to realize that exon 20 insertions are the third most common group of EGFR mutations and comprise approximately 5% of all EGFR mutations. Now, historically, the EGFR targeted drugs which have been the first, second, or third generation tyrosine kinase inhibitors have largely shown efficacy for the two common types of EGFR mutations, namely the exon 19 deletions and the exon 21 L858R point mutation. Exon 20 insertion mutations thus did not have any effective targeted therapy so far. But now, both of these drugs, amivantamab and mobocertinib, have shown very promising results for pretreated patients with this molecular aberration and therefore may be used in view of standard second line therapy. Similarly, in the case of KRAS G12C mutation, before this, there was no effective targeted therapy, but now sotorasib, based on the CodeBreaK 200 trial, appears to be a very valid option in view of standard second-line therapy.  Brittany Harvey: Excellent. So then, what do these new treatment options mean for patients with stage IV non-small cell lung cancer and an exon 20 insertion or a KRAS G12C mutation?  Dr. Navneet Singh: For patients with stage IV NSCLC and harboring an EGFR exon 20 insertion, the availability of two specific targeted drugs will improve the treatment options available following standard first-line therapy. Furthermore, ongoing trials for these agents in the treatment-naive setting may eventually lead to a scenario wherein such patients may be treated upfront with targeted therapy rather than chemotherapy or chemoimmunotherapy, analogous to how patients with the common EGFR mutations are treated. The ultimate aim of precision medicine is to offer the most effective treatment based on biomarker expression and targeted therapies in comparison to chemotherapy because these lead to better treatment outcomes and lesser side effects. Brittany Harvey: Absolutely. The goal of better outcomes with less side effects is what we're looking to achieve here. So then, finally, as this is a living guideline, what emerging therapies or targets is the panel monitoring for future guideline updates? Dr. Navneet Singh: As was already said, the expert panel eagerly awaits data from ongoing trials which are assessing the efficacy of drugs targeting the EGFR exon 20 insertion mutations, namely amivantamab and mobocertinib as first-line therapy, as also the drugs which target the KRAS G12C mutations which is sotorasib and adagrasib in the treatment-naïve setting. Ultimately, the optimal sequencing of therapies needs to be established in advanced and metastatic non-small cell lung cancer for several of the oncogenic driver alterations other than classical EGFR mutations and ALK and ROS-1 rearrangements. These include the EGFR exon 20 insertions and other uncommon EGFR mutations, the BRAF V600E, KRAS G12C, the HER2, and the MET exon 14 skipping mutations as well as the RET and NTRK fusions.  Brittany Harvey: It sounds like the living guideline expert panel will be busy moving forward then. So I want to thank you so much for your work to update this living guideline and thank you for your time today, Dr. Singh.  Dr. Navneet Singh:  Thank you so much, it was a pleasure being here. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.03.547586v1?rss=1 Authors: Salazar Leon, L. E., Brown, A. M., Kaku, H., Sillitoe, R. V. Abstract: Purkinje cell dysfunction causes movement disorders such as ataxia, however, recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxia mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity is unaltered in the mutant mice, although their sleep parameters and ECoG patterns are modified. The L7Cre;Vgatfx/fx mutant mice have decreased wakefulness and rapid eye movement (REM) sleep, while non-rapid eye movement (NREM) sleep is increased. The mutant mice have an extended latency to REM sleep, which is also observed in human ataxia patients. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.29.547140v1?rss=1 Authors: Wei, S., Jiang, A., Sun, H., Zhu, J., Liu, X., Xu, Z., Zhang, J., Jia, S., Shang, Y., Fu, X., Li, G., Wang, P., Xia, Z., Jiang, T., Cao, A., Duan, X. Abstract: Large-scale brain activity mapping is important for understanding the neural basis of behaviour. Electrocorticograms (ECoGs) have high spatiotemporal resolution, bandwidth, and signal quality. However, the invasiveness and surgical risks of electrode array implantation limit its application scope. We developed an ultrathin, flexible shape-changing electrode array (SCEA) for large-scale ECoG mapping with minimal invasiveness. SCEAs were inserted into cortical surfaces in compressed states through small openings in the skull or dura and fully expanded to cover large cortical areas. MRI and histological studies on rats proved the minimal invasiveness of the implantation process and the high chronic biocompatibility of the SCEAs. High-quality micro-ECoG activities mapped with SCEAs from rodent brains during seizures and canine brains during the emergence period revealed the spatiotemporal organization of different brain states with resolution and bandwidth that cannot be achieved using existing noninvasive techniques. The biocompatibility and ability to map large-scale physiological and pathological cortical activities with high spatiotemporal resolution, bandwidth, and signal quality in a minimally invasive manner offer SCEAs as a superior tool for applications ranging from fundamental brain research to brain-machine interfaces. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546557v1?rss=1 Authors: Goldstein, A., Wang, H., Niekerken, L., Zada, Z., Aubrey, B., Sheffer, T., Nastase, S. A., Gazula, H., Schain, M., Singh, A., Rao, A., Choe, G., Kim, C., Doyle, W., Friedman, D., Devore, S., Dugan, P., Hassidim, A., Brenner, M., Matias, Y., Devinsky, O., Flinker, A., Hasson, U. Abstract: Humans effortlessly use the continuous acoustics of speech to communicate rich linguistic meaning during everyday conversations. In this study, we leverage 100 hours (half a million words) of spontaneous open-ended conversations and concurrent high-quality neural activity recorded using electrocorticography (ECoG) to decipher the neural basis of real-world speech production and comprehension. Employing a deep multimodal speech-to-text model named Whisper, we develop encoding models capable of accurately predicting neural responses to both acoustic and semantic aspects of speech. Our encoding models achieved high accuracy in predicting neural responses in hundreds of thousands of words across many hours of left-out recordings. We uncover a distributed cortical hierarchy for speech and language processing, with sensory and motor regions encoding acoustic features of speech and higher-level language areas encoding syntactic and semantic information. Many electrodes including those in both perceptual and motor areas display mixed selectivity for both speech and linguistic features. Notably, our encoding model reveals a temporal progression from language-to-speech encoding before word onset during speech production and from speech-to-language encoding following word articulation during speech comprehension. This study offers a comprehensive account of the unfolding neural responses during fully natural, unbounded daily conversations. By leveraging a multimodal deep speech recognition model, we highlight the power of deep learning for unraveling the neural mechanisms of language processing in real-world contexts. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.22.546174v1?rss=1 Authors: Verkhlyutov, V. M., Vvedensky, V. L., Gurtovoy, K. G., Burlakov, E. O., Martynova, O. V. Abstract: Speech recognition from EEG and MEG data is the first step in the development of BCI and AI systems for further use in the decoding of inner speech. Great achievements in this direction have been made with the use of ECoG and stereo-EEG. At the same time, there are few works on this topic on the analysis of data obtained by nonin- vasive methods of brain activity registration. Our approach is based on the evaluation of connections in the sensor space with the extraction of the MEG connectivity pattern specific to a given segment of speech. We tested our method on 7 subjects. In all cases, our processing pipeline was sufficiently reliable and worked either without recognition errors or with few errors. After "training" the algorithm is able to recognize a frag- ment of spoken speech in a single presentation. For recognition, we used MEG recording segments of 50-1200 ms from the beginning of the word. A segment of at least 600 ms was required for high-quality recognition. Intervals longer than 1200 ms degraded the quality of recognition. Band- pass filtering of MEG showed that the quality of recognition is higher when using the gamma frequency range compared to the low-frequency range of the analyzed signal. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Age is a main factor when determining cancer care. In this ASCO Education podcast we speak to one of the top leaders in treatment for older patients who has also credited mentorship as a foundation for his career. Dr. Hyman Muss describes his childhood in Brooklyn, serving as a general physician for troops in Vietnam (6:18), the doctor who influenced his choice of hematology and oncology (7:48) and creating one of the first geriatric oncology fellowships in in the country (21:58).  Speaker Disclosures Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical Dr. Hyman Muss: None More Podcasts with Oncology Leaders  Oncology, Etc. – Devising Medical Standards and Training Master Clinicians with Dr. John Glick Oncology, Etc. – Rediscovering the Joy in Medicine with Dr. Deborah Schrag (Part 1) Oncology, Etc. – In Conversation with Dr. Richard Pazdur (Part 1) If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Pat Loehrer: Welcome to Oncology, Etc., an ASCO Education Podcast. I'm Pat Loehrer, director of Global Oncology and Health Equity at Indiana University.  Dave Johnson: And I'm Dave Johnson of Medical Oncology at the University of Texas Southwestern in Dallas, Texas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of our podcast is to introduce listeners to interesting and inspirational people and topics in and outside the world of Oncology. We have an inspirational guest today. Pat?  Pat Loehrer: If you ask anyone who's achieved any level of success and how they've achieved it, most likely they'll mention a number of people who've influenced them along the way. Quite often, these people reflect on their mentors, and after a certain time of accomplishment and reflection, they begin to mentor others. This is very much what our next guest has done. Dr. Hyman Muss has been a mentor to me and to Dave, and he's one of the most outstanding, wonderful people in the world, and we're so excited to have him today.   Dr. Hyman Muss served in the US Army in Vietnam, where he was awarded the Bronze Star Medal. He's an experienced Clinician Scientist, the Mary Jones Hudson Distinguished Professor of Geriatric Oncology at the University of North Carolina School of Medicine, and the Director of Geriatric Oncology Program at the UNC Lineberger Comprehensive Cancer Center Program. His interest in education and research is focused on cancer and older patients, and he is internationally recognized in this area. He's been the co-chair of the Alliance Committee on Cancer and Older Adults and won the BJ Kennedy Award from ASCO in Geriatric Care. His particular interest in research expertise is in the care of breast cancer patients, with a focus on the management of women who are of older ages. He's had a major interest in breast cancer survivorship and long-term toxicity of treatment and also served as the co-chair of the Breast Committee for the Alliance Group. He serves as a mentor for medical students, medical residents, junior faculty, and more recently, his Geriatric Oncology fellows. He served on the Board of Directors of the ASCO Foundation and on the ABIM, the American Board of Internal Medicine, where both Dave and I were privileged to work with him and witness his leadership and his deep breadth of knowledge.  Dr. Muss, thanks for joining us today. Dr. Hyman Muss: What a pleasure to be here. Thank you so much for inviting me. My mother would have loved the introduction.  Pat Loehrer: Well, speaking of that, tell us a little bit. You grew up in Brooklyn, so tell us a little bit about your parents. Your father was a dentist, I think, and your uncle was a general practitioner. So give us a little bit of the early life of Hy Muss. Dr. Hyman Muss: So I grew up in Brooklyn, New York. I was born and bred there. I went to Brooklyn Technical High School. I almost went to Brooklyn College, but I came back and went to Downstate Medical Center, which was just terrific. My tuition was $600 a year, but that's another story. My parents lived in the same neighborhood. My dad was a dentist, so we knew all the people. My uncle was the GP. You came into their office, sat down, and they saw you anytime, day or night, almost 24/7, something we're probably not going back to, but they had a profound influence on me. My uncle, as a GP, used to take me on house calls in Brooklyn when they were done, and he had an old Buick with MD plates. And I would go into these families, and they loved him, and they would give me ice cream and things. Maybe that's what made me a doctor. But it was a terrific and indelible experience. I had terrific parents. In those days, doctors and medical people usually lived in the same neighborhoods as their patients, so they really knew their people well. It was a terrific upbringing. I got to love medicine and have never had a look back. Dave Johnson: So your inspiration for a career in medicine obviously started at home. Tell us more about your formal education. You mentioned your high school education. What about college? And shortly thereafter?  Dr. Hyman Muss: Yeah, well, I went to Lafayette College. I was not the best high school student, but I had good college board scores or whatever they called them then. And I went to Lafayette and I thought I was going to be a chemist, a chemistry major. But I took enough premed courses and I spent a summer in a lab building cyclic ketones. And everybody was outside sitting on the lawn of the campus. And I was in there with all these distillation apparatus, and I said, “I don't think I can do this the rest of my life.” So I applied to medical school, and I got into several medical schools. But my father at that time was dying of metastatic bladder cancer. He had been a heavy smoker, and he was still working as a dentist. He worked until the day he unfortunately died. But I got into Downstate. We lived in Brooklyn, and my uncle, the GP, said, "Hy, you need to come home and help take care of your dad." I'm an only child, so I did. And I had a wonderful experience at Downstate.   Several years ago, I was listening to NPR and heard that one of my professors had won the Nobel Prize. Dr. Furchgott in physiology, one would have never thought. And I had a wonderful education and subsequently got into what was then Peter Bent Brigham in Boston, did my internship and residency there, joined the army and medical school, so I wasn't drafted, it was a program then. And then after first year of residency, I went to Vietnam, worked with an artillery battalion, a mystical experience, but no regrets. And then subsequently came back and did hematology and oncology at Brigham and at what was then the Jimmy Fund and Sidney Farber Cancer Center. And Tom Frei had just come. And I did hematology with a guy named Bill Moloney in Boston at Harvard. I'll tell you, a wonderful man. He was like a surrogate father. My dad had died by then, and I just feel I've had every opportunity to have a wonderful education and terrific mentors along the way. Dave Johnson: So we want to ask you about both of those gentlemen, but I would like to just, if I may, drop back to your experience in Vietnam. What was that like?  Dr. Hyman Muss: Well, I was 27 years old and I was put as the doctor for 500 men in artillery. My job was to take care of the general health of the troops. Fortunately, we didn't have many casualties. It wasn't a front war like my uncle, who was a GP actually in World War II, landed in Normandy about a week later and went all through World War II as a doctor. But Vietnam was an unusual war, there wasn't really a front. So my experience was I would go out to fire bases, which were units of about 100 men in the jungle, go out three days in a week in a helicopter, do sick call, check people. I dealt with really alcohol problems, unfortunately, a lot of drug problems. You had young people with really not a lot to do during the day, nothing much to do, and no real goal of being there. I did that for a while, and actually, the reason I got the Bronze Star was because I set up– It was nothing like standing in front of a machine gun. I'm not that kind of brave guy, but I set up a drug amnesty program so I got a lot of support from our regular field people to do this, so we didn't have to keep sending kids home with dishonorable discharges. And I learned a lot. I think we were reasonably successful. I learned a lot about artillery. I think overall it was a great experience in my life. Dave Johnson: Tell us how your interest in hematology and oncology originated. Where did that come from?  Dr. Hyman Muss: When I was an intern at the Brigham, Dr. Moloney was a very famous Harvard professor. He had studied war casualties after Hiroshima, he was one of the people that found the Philadelphia chromosome in CML. He was a guy that rounded on every single one of his leukemia patients every day. So I was an intern. So in those days I would go and see all the hematology people rounding because all the acute leukemia patients and all the serious cancer patients were right on the floors, right on the wards. We had 17-bed wards, and then we had some private rooms. And he loved what he did. And before I left for Vietnam, we didn't have Ara C and daunomycin. So every leukemia patient I saw died. This is '68 to '70. Yet we tried all these different regimens. Occasionally you got someone who did well for six months, a year. But his bedside manner was absolutely wonderful to me. He knew all the patients. He'd ask them about where they lived in Boston. His humanism was terrific, and yet I loved the diseases he treated. The stakes were high. We didn't have good treatment, and I decided that that's probably what I want to do.   So when I was in Vietnam, I applied and got back in the Hematology Fellowship and came back and did that. I saw Ara C and daunomycin. I gave the chemotherapy to them, and he'd say, "Go up and treat Harry Smith with Ara C and daunomycin." I had the syringes in my pocket, guys. Forget about hoods and mixing. And I'd go up and treat them and the marrow would be gone within four or five days. I did a bone marrow. They published their regimen in the New England Journal called COD, C-O-D because they also gave vincristine. So it was cytarabine, vincristine, and daunomycin, the COD regimen. It fit Boston. And I saw it was like the emergence of cisplatin after Larry Einhorn. You saw people that never survived going into remission and I saw some remissions in AML and it cemented it.  About my second year of residency, we had a child. I was running out of money. I was being paid $6,000 a year and I had the GI Bill. I went into Dr. Moloney and he talked with Dr. Franny Moore, who was head of surgery at the Brigham, and they made me the Sidney Farber Research Fellow, doubled my salary and I had to go to the Jimmy Fund and see cancer patients. And it so happened that was when Tom Frei came to Dana-Farber. And so I started rounding with Dr. Frei and seeing those patients. And I think the first day I walked in, I knew I wanted to do more than just leukemia because I saw groups of patients with every disease. We treated everybody with CMFEP, it didn't matter what cancer they had. And I just loved it and said, "My God, there's so much we can learn. What a great career." And so that got me into the oncology portion.   And then I was offered to stay at Harvard. They were going to make me an assistant professor, but they wanted me to do lab work. And I knew my personality, it just wasn't for me. I worked with a lovely guy named Frank Bunn, one of the world's great hem guys in his lab, and he's still a close friend in his 80s. And he told me one day, he said, "Hy, I don't think the lab is for you." And he actually helped me get my first job at Wake Forest University, which turned out to be wonderful. So that's how I ended up with my circuitous in HemOnc. And it's really from great mentors, it's from Bill Moloney, it's from Tom Frei, Dave Rosenthal, tons of wonderful people along the way that not only taught me a lot, but they seemed to love what they do, which is a gift in life to love what you do and love the people you're doing it with. They instilled that in me. Pat Loehrer: From there you went to Wake Forest and there's a couple of colleagues down there, I believe, that inspired you, Charlie Spurr and Bill Hazzard, who was the founding founder of geriatrics. Tell us about that experience and how'd that shape your life.  Dr. Hyman Muss: I was looking for a clinical job and I looked at Rochester, and I got snowed in one night in Wake Forest, and I said, “Where's the contract?” And I signed it. And my mother, who was living in New York City, didn't know where North Carolina was. My mother was from a family, was born over a candy store in Greenwich Village, and said, “Where are you going?” And then I showed her where it was, and she says, “They're going to kill you down there.” And it turned out to be one of the best decisions of my life. My wife Loretta, who both of you know so well, we got out of our VW with our dog and our daughter when we moved here, and VW bug, by the way, not a van, and she cried. It turned out it was one of the best opportunities.  Charlie Spurr was an iconic oncology leader. He actually did some of the early work on nitrogen mustard in Chicago during the war, the first chemotherapy drug. He was a terrific leader. He had patients programmed in on those IBM punch cards. He had little cards for the protocols, CMFEP, CMF, AC on little laminated index cards. I learned so much from him, and he was to me, great leaders and great mentors morph from things they do themselves to teaching other people, and whose brains have the ability of having the same dopamine shot when you see one of your fellows or young faculty present a wonderful study as you do. And your brain isn't saying, “I wish I was up there.” It's saying, “Isn't this so cool that this young man or woman or fellow or medical student is doing such a wonderful job?” And I had something to do with providing the soil for this seed to grow. That's the kind of guy he was. And so it was wonderful there.  And as I moved on, we got a new Chief of Medicine, Bill Hazzard. And I still hear from Bill on rare occasions, but Bill was one of the first geriatricians in the United States. He wrote the textbook, and his wish was that all the faculty and all the specialties get involved in a geriatric project. And so I had all those little index cards, and I looked and saw how many older people with metastatic breast cancer we'd given chemotherapy to. And these were little protocols, nothing like the protocols today, no 50-page consent forms, 50 pages of where your data is stored. They were like, here's the treatment, here's the dose mods. And I looked at those 70 patients with one of our residents, Kathy Christman, she may be retired now, but in any event, we wrote a paper and showed the old people did as well as the young with breast cancer. And we published it in JAMA. And it's one of the few papers in my career, I got no reviewers. They accepted the paper. I got no reviewers. So because I'm from Brooklyn, and my English is not what it should be, I had my friends read it to just make sure I didn't say anything egregious. But it got published and the next thing I know, my friends in medical oncology in the state were calling me. They said, “I got a 75-year-old woman here.” I'm saying, “Guys, I just wrote this paper. I really don't know anything about older people.” But slowly, with Bill Hazzard and others, I got more and more interested. I started reading about Geriatrics and I ended up making it a focal point of my career. It was kind of happenstance. And Bill was a wonderful mentor.  And then as I subsequently moved on, I worked with terrific people like Harvey Cohen, Lodovico Balducci, and Martine Extermann, all of them heavily involved with ASCO over the years as well, and B.J. Kennedy. They were wonderful to work with. And BJ was inspirational because BJ would get up at an ASCO meeting and he'd say when he saw the age cut off, he'd say, “How come you didn't let old people on that study? There'd be 1000 people in the audience.” And so he really was a great mentor. And I had the bittersweet opportunity of writing his obit for JCO years ago and kept up with his family a few years, but he was a wonderful man. Dave Johnson: I'm just reflecting on the fact that today, patient registries are sort of mainstream, but certainly in the ‘70s, ‘80s, even into the ‘90s, having a list of patients with a particular disorder seemed almost novel in many respects. And to have that was a godsend.  Dr. Hyman Muss: It was a godsend. I still remember those little file cards. And he called it the Oncology Research Center and it was a godsend. And you've got to remember, this is like ‘74, ‘75, it's a long time ago. Dave Johnson: So many of our listeners may not be as familiar with Wake Forest as they are with Duke and North Carolina, the other medical schools located there. But you were at right at a point where I mean, it was one of the top oncology programs in the country at that time. Still is, I don't mean to diminish it, but there was a who's who of people there at the time. And you were also involved in creating, I think, one of the first cooperative groups of sorts. It was the Piedmont Oncology Group. Tell us about that.  Dr. Hyman Muss: Oh, yeah, well, that brings back memories. So the NCI at that time wanted to get more, I think, rural and other smaller places involved in research. And they put out an RFA to form like regional cooperative groups. And we formed the Piedmont Oncology Association, the POA. We actually did well for a few years. We wrote some really good studies. We got one or two New England Journal articles. I worked with all the people, mainly in the community, community docs who would go on, and put people on the protocol. I mean, I looked at all the X-rays and scans in a lot of these patients myself as part of the studies we did. And it turned out to be a wonderful organization and it's still run today by Bayard Powell, who is one of our terrific fellows who's the head of Oncology at Wake Forest.  But after a while, we just couldn't compete with CALGB, of which I was a member of also, and ECOG and SWOG, even North Central Group, which was kind of formed in a similar venue, eventually merged. So we did a wonderful job for a while but the truth is we just didn't have the manpower to write studies for every disease site. So eventually we kind of petered out as a clinical trials group. But it's been maintained for educational programs and it's really served as a good resource for a lot of good education for the community oncologists who give most of the care in this country in the state. So it's been good. I think Pat kind of exceeded us with HOG, the Hoosier Oncology Group, which was in a similar vein. But it was a great experience and it was all Dr. Spurr, who thought of doing this and built it.  Dave Johnson: Certainly, it was inspirational in many people in and outside of Wake Forest. So with such an idyllic life, what in the world possessed you to move north to Vermont?  Dr. Hyman Muss: Well, you get this urgent life. You want to be a leader, you want to be a chief. Now, I tell younger people, if they love what they do, don't do it. So I got a wonderful opportunity at the University of Vermont to go up there and be Head of HemOnc. Chief of Medicine was a terrific guy, Burt Sobel. The university at that time, at one time it had a wonderful Oncology program. It had a federally funded cancer center with Irwin Krakoff and Jerry Yates, two other iconic guys. I don't know what the politics were but it had lost a tremendous amount of faculty, especially its clinical faculty, and they needed to rebuild it. And I went up and I thought, “Well, I'm in my 50s. This is going to be a great opportunity. If I don't do it now, I may never get the chance.” So I went up there and actually, it was a great opportunity. We hired terrific people. We got CALGB and we participated. We had actually a very good accrual for a small place and we had a very small but very effective cancer center. So it turned out to be a really good experience.  I worked with wonderful people. I recruited some wonderful people. But over time, the issues of the business of medicine, all the issues that happened, I'm saying I'm kind of losing my focus on clinical care and clinical trials, which I love to do. I don't need to tell either of you. I mean, Dave, you've been chief and department chair and Pat has run cancer centers. After a while, the administrative tasks just were so overwhelming and I didn't enjoy them, that I said, “I've got to get back in some type of more clinical focus.” And that's when I decided to look around and fortunately found what's turned out to be a dream job at UNC.  But it was a time of life. Maybe my ego got in the way of my logic. I don't regret it. I met and I think we rebuilt a wonderful clinical program. But you realize some of the resources of big places with-  we never had the research infrastructure to hire a lot of people and get big programs going on and great translational programs, just didn't have the funding. But it was great, and I have no regrets. And I learned how to tolerate the cold weather. And I have a lovely daughter, Sarah, who still lives up there. So we get back occasionally. And I've kept up with a lot of the people there. There are some wonderful people at UVM.  Pat Loehrer: From there, though, you were pulled down to North Carolina, where you've, again, built an incredible breast program there is outstanding. But you've created a Geriatric Oncology program, one of the first geriatric fellowships in oncology in the country. So tell us a little bit about that and what you feel may be your legacy is there at North Carolina.  Dr. Hyman Muss: Well, I had the opportunity over the years when I was at Wake, really, I got to know Shelley Earp, who's our cancer center director. I think maybe you were close to him, Pat. The longest surviving cancer center director on the planet, or among them. And we were good friends. And North Carolina's legislature actually gave the University of North Carolina substantial funding to improve cancer care in North Carolina, not just research. And so I had talked with Shelley about maybe moving, and because of the generosity of the state, really, he was able to really get me going, start a Geriatric Oncology program. And what I wanted to do was develop trials. As Dave says, I built a registry in 2009 here for older cancer patients using geriatric assessment. I have 2000 patients, which has been a resource for all types of faculty and fellows, and students to write papers. But I was able, with the support, to do things like this right from the get-go. And plus, I joined probably one of the best breast groups on the planet with Lisa Carey and Chuck Perou, and Larry, terrific people, Claire Dees. I had great luck in doing this, so I was able to really focus, get great support from my colleagues to build studies focusing on older people.  And then I had the great fortune of meeting Ned Sharpless, our prior NCI director. And Ned is one of the world's great aging biologists. And I don't mean aging as an adjective, he's really been a master on why we age, the biology of aging, cell senescence. So Ned taught me all about cell senescence and the mechanisms, especially the gene expression p16, which is like our own CDK inhibitor. And so I was able to start using his lab, collect samples, treat people with chemotherapy, follow them off with geriatric assessment. It was a great opportunity to do that here, and we got a lot of studies going and we showed what the pediatricians have known for years, that chemotherapy dramatically ages people, not just children, but adults. But it also allowed me to work with my colleagues in lymphoma and lung cancer to do little studies along the way.  And we eventually then built a T32 program. We got a T32, which we're kind of completing now our first five years to train oncology specialists in geriatrics. So the way we do it is they can be surgical oncologists, GU, we had a GYN oncologist, medical. With their HemOnc training, they do a year where they work with the geriatricians, so they go on geriatric inpatient service for a month and they really learn about older people. And part of it is a project. So we've been able to build that and develop a lot of programs with that. And I should say we've been very successful with mentorship and with ASCO support for things like YIAs, the late and great Arti Hurria, who absolutely an amazing woman. Some of her legacy at ASCO, the YIAs, and things. We've been successful in applying for some. So we've been able to build a whole spectrum of med and hematologists. We have an interest in Myeloma and AML focusing on older people. We've been able to build a whole team approach, including translational projects related to older people. And it's just been a great opportunity, and hopefully, my legacy here will be, too, and I'm working on it.  We have a wonderful guy, Bill Wood, who is very effective and has built this incredible coaching program to continue this legacy. Like many of us in this field, we are bothered because we all know the stats, we all know that first slide of the demographics of cancer, and yet it's been very hard in our culture to provide a lot of the services and build the clinical trials we need to best care for older people. It's still a major problem in this country. So as I cut back on my clinical care, I'm going to still advocate to try to improve the care of older people. Do geriatric assessment, build it into your clinical programs, get your hospitals to support you, convince them, build business plans, et cetera. And hopefully, that'll be my ultimate legacy, that we've made greater awareness of the older people, other than the usual stats, and we're really trying to care for them in a much more global sense, in a much more holistic sense than we've done. I hope we'll be successful. It's a slow haul, but we've got lots of great young people coming up through the pipelines, ASCO has been a great player in this. Many of you know people like Supriya Mohile and William Dale, Heidi Klepin, people, the next generation that's going to keep building this. So I hope the legacy will be that we get more buy-in, more interest, more trained people in other oncology-related subspecialties RadOnc, SurgOnc that will really focus on the care of older people. Dave Johnson: I don't think there's any doubt that that will be a part of your legacy Hy, but I think your legacy will be much broader than the world of geriatric oncology. Your mentorship leadership, your clinical skills, your educational capabilities, all of that will certainly last for many, many years in the future.  Well, I don't want to bring up a touchy topic, but you yourself are geriatric and we're wondering what your plans are for your semi-retirement. I recognize you're not retiring, but what do you like to do outside of medicine? Dr. Hyman Muss: I'll tell everybody who's interested in hearing this. On Tuesday, I had my 80th birthday.  Dave Johnson: Congratulations.  Dr. Hyman Muss: And I think I'm one of the most blessed guys. I'm pretty healthy. I married up -  my wife Loretta, who both of you, Pat Loehrer and Dave Johnson, know well.  Dave Johnson: Yeah, you definitely married up.  Dr. Hyman Muss: Yes. It's really carried me most of my life. She's great and so she flew up our three kids and we celebrated and I'm very fortunate. I have the enthusiasm and strength to do more clinical medicine. But I think the time has come for me to cut back my clinical medicine, so I'm going to do that in June. The hardest thing I've done is say goodbye to so many of my patients here.  We've been blessed. We have a lovely family. We're pretty close. I'm never bored, probably you two know well, I love to do things like fishing, outdoor stuff. I've really gotten into woodworking, so I'm not going to be bored. But there will be a small piece out of me when I walk out of that clinic in June. I know that and my two close psychiatry friends think it's going to really be a hard fall, but I don't think so. I still have some grants. In fact, I'm working with a fellow in City of Hope, Mina Sedrak, who's been very involved in ASCO, too. We are hoping to get an R01 looking at senolytic drugs that may prevent aging, and exercise in older women with breast cancer to see if we can reverse the trends of chemo. So my brain is still on that stuff, but the clinical care is going to be tough.  I had a note and for some reason, we talked about so many things. I wanted to mention that one of my great opportunities was joining the CALGB and then the Alliance and getting the support of Dr. Schilsky, Rich Schilsky, who's been one of the icons of ASCO to build cancer in the elderly working group with Dr. Harvey Cohen at Duke. And Harvey is one of the world's great geriatricians. And using that to get studies done, to incorporate studies with Arti Hurria on geriatric assessment, and really have it as a place where a lot of younger investigators could get started on a career in geriatric oncology. And that was really a great opportunity. It was kept on by Dr. Bertagnolli, who now is our NCI director, and I think was really the first group to really give good support for this. Dave Johnson: So we want to thank you very much for being our guest today.  We also want to thank our listeners of Oncology, Etc. This is an ASCO Educational Podcast where we talk about oncology medicine and much more. So if any of our listeners have an idea or a guest they would like for us to interview, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, visit ASCO's website at education.asco.org.   Thanks again for being our guest, Hy.  Dr. Hyman Muss: My pleasure. Thank you so much. 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.  

El Dr. Homero Fuentes de la Peña, oncólogo médico, presidente de ProOncavi A.C. en Baja California, México, nos habla sobre lo más destacado en el Congreso Anual ASCO 2023 del día 4, resaltando los siguientes estudios:   Cáncer de próstata  La priorización y secuenciación del tratamiento para el cáncer de próstata avanzado se ha convertido en un tema de gran importancia debido a la amplia gama de terapias y estrategias disponibles actualmente. En los siguientes temas se explora la forma de establecer prioridades y determinar el orden de administración de estas opciones terapéuticas, con un enfoque especial en las enfermedades hormonosensibles y la terapia basada en biomarcadores:   Cuando más es más: Intensificación del tratamiento para el cáncer de próstata hormonosensible. Cuando menos es más: Reduciendo la exposición a la terapia sistémica para el cáncer de próstata hormonosensible. Momento de la inhibición de PARP para el cáncer de próstata con defectos en la reparación por recombinación homóloga. Cáncer de mama   SONIA: Estudio fase III, aleatorizado, que evaluó a pacientes pre y posmenopáusicas con cáncer de mama avanzado RH+/HER2- que no habían recibido tratamiento previo, para recibir terapia con un inhibidor de aromatasa no esteroideo (IANE) + iCDK4/6 seguido de fulvestrant (F) al progresar o IANE seguido de F + iCDK4/6 al progresar. La elección entre los iCDK4/6 disponibles (abemaciclib, palbociclib, ribociclib) fueron un factor de estratificación y quedó a discreción del médico tratante. El objetivo primario fue el tiempo desde la aleatorización hasta la segunda progresión objetiva de la enfermedad o la muerte. Los objetivos secundarios incluyeron la supervivencia global (SG), la seguridad, la calidad de vida y la rentabilidad. TROPiCS-02: Estudio fase III, aleatorizado, que evaluó el uso de sacituzumab govitecán vs. el tratamiento a elección del médico (capecitabina, eribulina, vinorelbina o gemcitabina) en pacientes con cáncer de mama irresecable, localmente avanzado o metastásico, RH+/HER2-con un estado funcional ECOG de 0 o 1, que fracasaron al menos dos regímenes de quimioterapia anteriores. El objetivo primario fue la supervivencia libre de progresión de acuerdo con los criterios RECIST v1.1 mediante una revisión central independiente ciega y el objetivo secundario fue la SG. Eficacia de trastuzumab deruxtecán (T-DXd) en una paciente con cáncer de mama HER2+ con hipertensión intracraneal aguda por metástasis cerebrales: Efecto clínicamente significativo de T-DXd para tratar la invasión sintomática del sistema nervioso central en una mujer de 47 años diagnosticada con carcinoma ductal invasivo cT2 en junio de 2019.     Fecha de grabación: 05 de junio de 2023.                                         Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gulam Manji from Columbia University Irving Medical Center. Dr. Manji provides insight into his editorial published in the April 10, 2023 JCO issue: "Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” (10.1200/JCO.23.00039). His editorial focuses on the JCO Original Report, “Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial” by Tempero, et al on the APACT Trial. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Emily Zabor: Welcome to this JCO Article Insights episode for the April issue of JCO. This is Emily Zabor, one of JCO's editorial fellows. And today I am interviewing Dr. Manji from Columbia University on their editorial titled “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Dr. Manji, welcome to our podcast. You wrote this editorial to accompany the article, “Adjuvant Nab-Paclitaxel plus Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results from a Randomized Open-label Phase III Trial by Dr. Margaret Tempero and Colleagues.” That trial, called the APACT Trial, investigated the efficacy and safety of adjuvant nab-paclitaxel plus gemcitabine compared to gemcitabine alone in patients who had undergone resection for pancreatic ductal adenocarcinoma. So I wanted to ask if you could start by giving listeners a quick overview of the study design and the main findings from that trial. Dr. Gulam Manji: Yeah, sure, Emily. So, as you pointed out, it was a randomized phase III study in patients who had resected pancreatic carcinoma. The primary endpoint was independently assessed disease-free survival. Additional endpoints included investigator-assessed disease-free survival, overall survival, and safety. And we'll get back later on as far as the importance of investigator-assessed versus independently-assessed disease with survival because I think that that's the main point of discussion for today. The enrollment criteria were fairly stringent and included patients with macroscopic complete resection, ECOG performance status of either 0 or 1, and the peripheral tumor markers of CA 19-9 being less than 100. And patients were required to initiate adjuvant chemotherapy within 12 weeks. Patients received standard gemcitabine at 1000 milligrams per meter square, either with or without nab-paclitaxel of 125 milligrams per meter square once weekly for three weeks during every four-week cycle. Emily Zabor: Great. So I think that the main thing that we wanted to talk about today, and one of the main points you discuss in your editorial is the difference between the primary endpoint of independently assessed disease-free survival and the secondary endpoint of investigator-assessed disease-free survival. So can you describe the difference between those endpoints, how they were defined, and how they differed? Dr. Gulam Manji: Sure. So, independently-assessed DFS was determined by a radiologist who was blinded to treatment assignment, and new lesions followed RECIST 1.1 criteria. In contrast, the investigator-assessed recurrence was determined by the treating physicians using all available clinical information. So that could be abdominal pain, anorexia, probably elevation of peripheral tumor markers. And the other important aspect to the study is that the independent review was not performed in real-time to confirm investigator assessments. So patients who started subsequent therapy after recurrence by treating investigators were censured for the independently-assessed DFS analysis. So in this trial, 866 patients were randomized. And patients who are randomized to the experimental arm had a median independently assessed DFS of 19.4 months, while patients randomized to the control arm, which was gemcitabine alone, had a median DFS of 18.8 months. Now, when we compare that to the investigator-assessed DFS, the data looks quite different. Where the DFS was 16.6 months in the experimental arm compared to 13.7 months in the control arm. That is consistent with the five-year follow-up looking at the median overall survival, which was 41.8 months for the combination arm compared to 37.7 months for the gemcitabine alone arm. Emily Zabor: Okay, so there's some really interesting differences there. And I noticed that there were only 439 events according to the independently-assessed DFS versus 571 according to the investigator-assessed DFS. So that's a big difference in the number of events that I guess is coming from that additional censoring that was occurring due to the delay in the independently assessed endpoint. Is that right? Dr. Gulam Manji: Exactly. So you could envision a scenario where patients received chemotherapy and then on the investigator-assessed DFS, the investigators decided that the patient had recurred. However, that patient probably did not meet the RECIST or radiological criteria to determine that that patient had recurred. And hence, since it was not done in real-time, there was censoring that occurred for the independently-assessed DFS. So that's the reason why there was a difference in that number as you pointed out.  The decision to use independent DFS, disease-free survival, really was to remove investigator-associated bias and increase rigor to the study, which is commendable. However, unfortunately, that's not how we normally treat patients with aggressive cancer who have undergone surgical reception. And knowing that imaging modality is limited in identifying those patients, particularly in those that have peritoneal disease, or even more importantly, the patients who have recurrence within the surgical bed, I think is the issue.  Emily Zabor: Right. So the motivation behind selecting that endpoint was really good and well-motivated. Everybody wants to reduce bias and make sure we're taking out those kind of more subjective parts of identifying that. But it, unfortunately, missed some events as a result. Dr. Gulam Manji: Correct. I think that it delayed those events and that's what compromised the analysis because it was the limitations of the available modalities to determine when recurrence occurs. Emily Zabor: So how do these different definitions compare to other trials or previous trials? Dr. Gulam Manji: So previous trials that I'm aware of, it was the investigator-assessed DFS that had been used. And when you look at the data that was used in this trial, that concurs with what has historically been seen. And what I mean by that is that the original assumptions regarding DFS when this trial was being designed, used historical outcomes. Investigators see that DFS with adjuvant gemcitabine ranged anywhere from between 13.4 to 14.3 months. And the study had aimed to achieve a DFS improvement from 13.5 to 18.5 months. When you look at the investigator-assessed DFS, the ballpark of gemcitabine is very much in line with the previous historical data. So I think that the key discrepancy between the two DFS endpoints was likely a delay in accurately assessing disease recurrence when using the blinded radiological modality alone. And the second thing is, as you pointed out, a greater proportion of patients who were censored for independent assessments compared with those for investigator assessments was different. So that was between 40% versus 34%. So those two points, I think, were the key points that show the difference between independent versus investigator-assessed DFS and also that the independent-assessed DFS was not done in real-time. Emily Zabor: Yeah, that's really interesting and such a good point. And I think it really emphasizes how important it is to think carefully about these endpoint definitions in the design stage of these clinical trials and especially to think about when and why patients are getting censored and how that might impact the results.  So how do these results of this trial then, given the negative result of the primary endpoint, but that positive result on the secondary investigator-assessed endpoint, how do these fit in with other trials? And what do you think that means for patient treatment recommendations? Dr. Gulam Manji: Excellent point. So just to be clear, the APACT study did fail to meet its primary endpoint and hence gemcitabine and nab-paclitaxel were not indicated for patients in the adjuvant setting. The current standard of care are either modified FOLFIRINOX or gemcitabine combination with capecitabine. And those two regimens really remain a standard of care for patients. So what I do is for fit patients, I prefer modified FOLFIRINOX. However, in patients who are not as fit, gemcitabine in combination with capecitabine is the alternative.  Now, one could envision a scenario where gemcitabine and nab-paclitaxel may become relevant. It is, but only when I'm really pushed to do so, where I feel like there is no other regimen available optimally for a patient. And one could envision a scenario where you could have a patient who does not have the performance status to tolerate modified FOLFIRINOX and then you start that patient on gemcitabine in combination with capecitabine. However, I have experienced that that combination results in significant myelosuppression in patients in the United States. And then we have to do significant dose reductions or interruptions.  Now, in that case, where I feel like I'm reducing the dose of capecitabine to a point where the patient may not be potentially benefiting from that regimen, it's impossible to determine what dose would be efficacious when you're doing those dose reductions. That is the only scenario where I may be able to be pushed to consider gemcitabine and nab-paclitaxel, but only after also discussing with the patient the results of the current data and there being limited efficacy. Emily Zabor: That makes sense. So the treatment you would select would really depend on some patient characteristics and then how they do on the different treatments. Dr. Gulam Manji: Correct. Emily Zabor: So what do you think are the next steps for research in this area and in this disease?   Dr. Gulam Manji: I think that this clinical trial really demonstrated our inability to accurately pinpoint the time of disease recurrence using imaging modalities alone. And for patients who treat pancreas cancer, they would know that the recurrence patterns usually are either to the liver or to the peritoneum, or to the lung. However, in about 25% of the cases, the recurrence may be at the surgical site, and that's when things become tricky. After patients have undergone surgery, their scar tissue and the pancreas tumor is very dense, so it's difficult to determine that there's actually tumor growth. So that's where you really need help from other modalities. So should we get a PET scan? Is the patient symptomatic? Is a tumor marker going up in the absence of biliary obstruction? So all of those things need to be taken into account to truly pinpoint whether the patient has recurred or not. In peritoneal disease, you may need to ask the surgeons to help and have the patient undergo a laparoscopy to truly determine whether there is a peritoneal disease. And lastly, I think that incorporating ctDNA to better define whether there is a minimal residual disease will likely be a standard in the future. Emily Zabor: I see. Yeah, that makes sense. Incorporating some ctDNA biomarker information along with these really detailed clinical and possibly imaging assessments to determine recurrence seems like it would be really important in future trials to make sure you're capturing all of those recurrences accurately. Dr. Gulam Manji: Yeah, I think that that's critical before you can say that an adjuvant treatment is truly helping the patient. Emily Zabor: That's great. Well, I really learned a lot reading this article and speaking to you today. But before we end, is there anything else you'd like to share with our listeners?  Dr. Gulam Manji: Yeah, so I think we know that for a majority of patients who undergo curative resection, unfortunately, the disease recurs. And I think that that implies that, really, pancreas cancer is a systemic disease at the time of diagnosis. And despite aggressive adjuvant therapy, the median DFS, OS, and five-year survival rate show that we are impacting only a subset of patients with six additional months of chemotherapy. So I think that identifying predictive markers of response to systemic therapy, better selection of patients for surgery, perhaps using total upfront neoadjuvant therapy, an institution of maintenance therapy, and patients who are at high risk for recurrence, perhaps using ctDNA as a marker to determine who those high-risk patients are, all leads to help better design and identify patients who should really be treated systemically and patients who should undergo surgery. And lastly, with some glimmers of success from personalized vaccines may be on the horizon. And I'm hoping in the near future to treat minimal residual disease so that we can get the best outcome with minimal toxicity for our patients. Emily Zabor: That's great. That sounds like an exciting development for a disease that seems really tricky. Dr. Gulam Manji: Agreed. Emily Zabor: Well, thank you so much. It has been a pleasure speaking with you, Dr. Manji, and thank you so much for joining me today on this episode of JCO Article Insights.  This concludes the episode on the article “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Thank you for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr. Gulam Manji, MD, PhD is a medical oncologist at the Columbia University Irving Medical Center in New York.  Articles: Editorial: Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence? Original Report: Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial Find more articles from the April 10 issue.  

The early 1970's saw the start of the medical specialty we now know as oncology. How does one create standards and practices for patient care during that time? Dr. John Glick is a pioneer during the dawn of oncology. He says that early work involved humanity, optimism, and compassion, all of which were the foundation of his career. Dr Glick describes the clinical experiences that drove him to oncology (4:28), his rapport with patients, which was portrayed in Stewart Alsop's book Stay of Execution (9:21), and his groundbreaking work developing the medical oncology program at the University of Pennsylvania (12:22). Speaker Disclosures Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical Dr. John Glick: None More Podcasts with Oncology Leaders    Oncology, Etc. – In Conversation with Dr. Richard Pazdur (Part 1) Oncology, Etc. – HPV Vaccine Pioneer Dr. Douglas Lowy (Part 1) Oncology, Etc. – Rediscovering the Joy in Medicine with Dr. Deborah Schrag (Part 1)  If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.   TRANSCRIPT Disclosures for this podcast are listed in the podcast page. Pat Loehrer: Welcome to Oncology, Etc. This is an ASCO education podcast. I'm Pat Loehrer, Director of Global Oncology and Health Equity at Indiana University. Dave Johnson: And I'm Dave Johnson, a medical oncologist at the University of Texas Southwestern in Dallas, Texas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of our podcast is to introduce listeners to interesting people and topics in and outside the world of oncology. Today's guest is someone well-known to the oncology community. Dr. John Glick is undoubtedly one of oncology's most highly respected clinicians, researchers, and mentors. I've always viewed John as the quintessential role model. I will add that for me, he proved to be a role model even before I met him, which hopefully we'll talk about a little bit later.   To attempt to summarize John's career in a paragraph or two is really impossible. Suffice it to say, he is to the University of Pennsylvania Cancer Center what water is to Niagara Falls. You can't have one without the other. After completing his fellowship at NCI in Stanford, John joined the Penn faculty in 1974 as the Ann B. Young Assistant Professor. Some five decades later, he retired as the director of one of the most highly respected comprehensive cancer centers in the nation. Among his many notable accomplishments, I will comment on just a few. He established the Medical Oncology program at Penn and subsequently directed the Abramson Cancer Center from 1985 to 2006. Interestingly, he established the Penn Medicine Academy of Master Clinicians to promote clinical excellence in all subspecialties across the health system. He's been a driving force in philanthropy at Penn Medicine, culminating in his role as Vice President Associate Dean for Resource Development.  Over the past several decades, he has helped raise over half a billion dollars for Penn Med. We need you on our team, John. As a clinician scholar, John's research has helped shape standards of care for both breast cancer and lymphomas. For example, he pioneered the integration of adjuvant chemotherapy and definitive breast irradiation for early-stage breast cancer. In 1985, he chaired the pivotal NCI Consensus Conference on adjuvant chemotherapy for breast cancer. He also was a driving force in a clinical landmark study published in The New England Journal some 20 or so years ago about the role of bone marrow transplant for advanced breast cancer. Most impressive of all, in my opinion, is John's legacy as a mentor to multiple generations of medical students, residents, and fellows.   So, John, we want to thank you for joining us and welcome. Thought we might start by having you tell us a little about your early life, your family, your parents, where you grew up, and how you got into medicine. Dr. John Glick: Well, thank you for having me on the podcast, Pat and David, it's always a pleasure to be with you and with ASCO. I grew up in New York City in Manhattan. My father was a well-known dermatologist. He was my role model. And from the age of eight, I knew I wanted to be a doctor. Nothing else ever crossed my mind. But having seen my father's many interests outside of medicine, I realized from very early that there was much more to medicine than just science. And that really induced me, when I went to college, to major in the humanities, in history, art history, and I actually took the minimum number of science courses to get into medical school. That probably wouldn't work today, but it was the start of my interest in humanism, humanities, and dealing with people outside of the quantitative sciences.  Dave Johnson: So that's reflected in how we all view you, John. You're one of the most humanistic physicians that I know personally. I wonder if you could tell us about your interest in medical oncology, and in particular, as one of the pioneers in the field. I mean, there wasn't really even a specialty of medical oncology until the early 1970s. So, how in the world did you get interested in oncology and what drew you to that specialty? Dr. John Glick: Well, I had two clinical experiences that drove me into oncology. The first, when I was a third year medical student at Columbia PNS, my first clinical rotation in internal medicine, I was assigned a 20-year-old who had acute leukemia, except he was not told his diagnosis. He was told he had aplastic anemia, receiving blood and platelets, and some form of chemotherapy. And I spent a lot of time just talking to him as an individual, not just taking care of him. And we became friends. And he was then discharged, only to be readmitted about two weeks later. And in the elevator, the medical assistant had his admission sheet, and unfortunately, it was facing the patient, and it had his diagnosis, acute leukemia. So he came into the ward and he confronted me. "Why didn't you tell me I had acute leukemia?" Well, I couldn't say the attendees forbade me to do that. So I took what today we would call ‘the hit', and apologized. But it stimulated me to reflect that honesty with patients was extremely important, and that oncology was just in its infancy. We knew nothing about it. It was not considered even a specialty. I don't think we used the word "oncology."  But that inspired me to take an elective in my fourth year at PNS, at an indigent cancer hospital called the Francis Delafield Hospital. It only took care of indigent cancer patients, and there were wards, twelve patients in a ward, six on each side, and nobody would go see the patients. It was almost as if they were afraid that if they were to touch the patient, they would get cancer. And I started talking to the patients, and they were human beings, but nobody had told them their diagnosis. Nobody had told them if they were terminal. And there were a few patients who were getting a new drug at that time for multiple myeloma called melphalan, and they actually had relief of some of the symptoms, of their bone pain. But I realized that there was a huge void in medicine that I could possibly help to fill.  And that was the era of Vietnam, and so I applied to the National Cancer Institute to become a commissioned officer in the Public Health Service to avoid the draft, to be on a service with, at that time, some very notable oncologists Vince DeVita, Ed Henderson, Paul Carbone. I had read some of their papers, and I was lucky to be accepted. And I was a clinical associate at the National Cancer Institute. And that was life-changing because there every patient was considered to be potentially curable. The advances at that time using MOPP for Hodgkin's disease, C-MOPP for lymphoma, some treatments for leukemia. George Canellos pioneered the use of CMF for metastatic breast cancer. It was an amazing, amazing experience. That was in 1971 to ‘73. Oncology did not become a true specialty till ‘73, but my two years at NCI were formative.  However, I realized that there was something missing in my training. Everybody was considered curable, but I had never seen a patient with metastatic colon cancer, metastatic lung cancer. The radiotherapists there did not like to teach clinical associates, and I knew that there was a place called Stanford. And Stanford had Saul Rosenberg in medical oncology for lymphomas and Henry Kaplan in radiotherapy. So, everybody was going to California, and my wife and I packed up and went to California and spent a year at Stanford, which, combined with my training at the NCI, led me to the principles that guided my career in oncology; humanity, optimism, reality, compassion, and a love for clinical trials.  I was very, very fortunate to be there at the dawn of medical oncology shortly after I decided to go to Penn, which at that time did not have a medical oncologist. In fact, I was the only medical oncologist at Penn for four years and did every consult in the hospital for four years, much to the chagrin of my wife. But I was fortunate to have great mentors in my career: Paul Carbone, Vince DeVita, Saul Rosenberg, Henry Kaplan, among many, many others. And that impressed me about the importance of mentorship because my career would never have been where it was or is without these mentors. Pat Loehrer: John, just to echo what Dave said, you've been such a tremendous mentor for us. Dave and I particularly, you took us under your wings when you didn't know who we were. We were people in the Midwest. We weren't from any place shiny, but we really appreciate that. Dave Johnson: So, John, I mentioned at the very beginning that I met you before I met you, and the way I met you was through Stewart Alsop's book, Stay of Execution. He portrayed you as an extraordinarily caring individual, and it tremendously impacted me. It was one of the reasons why I chose oncology as a specialty. I realize it's been 50 or more years ago and most of our listeners will have no idea who Stewart Alsop was. And I wonder if you might share with us a little bit of that experience interacting with someone who was particularly well-known in that time as a columnist for The New York Times.  Dr. John Glick: His brother Joe Alsop and Stu Alsop were two of the most famous columnists at that time. Joe Alsop was a hawk right-winger who lived in the Vietnam War. Stewart was charming, was a centrist Democrat, wrote the back page for Newsweek for years. He and I had very similar educational backgrounds and interests. And we functioned on two different levels—one as a physician-patient, and then we became friends. And he and his wife adopted us into the Georgetown set.  And I received a lot of criticism for socializing with a patient. But over the years, I've been able to become friends with many of my patients, and I've been able to compartmentalize their medical care from our friendship. And I use the analogy if I was a doctor in a small town and I was the only doctor,  I'd be friends with people in town, with the pastor and likely the mayor. But I have always believed that patients can become your friends if they want it and if they initiated it.   Taking care of Stewart Alsop was an amazing, amazing experience. We didn't know what he had. People initially thought he had acute leukemia. In reality, he had myelodysplastic syndrome, but that hadn't been described yet. He had a spontaneous remission, which I rarely see, probably due to interferon released from a febrile episode, all his blasts went away in his marrow. One of my children's middle name is Stewart. But professionally and personally, it was an incredible experience. It taught me the importance of being available to patients. They had my home phone number. We didn't have cell phone numbers in those days. We had beepers, but they didn't work. And from that point on, I gave my home phone number to patients, and I actually trained my children how to answer the phone. “This is Katie Glick. How can I help you? My father's not home. You need my father? Can I have your phone number? I'll find him and he'll call you back.” Patients still remember my children and their way of answering the phone. Pat Loehrer: One of the things you did do is create this medical oncology program at Penn, which has graduated some incredible fellows that have become outstanding leaders in our field. But can you reflect a little bit about the process of creating something that was never created before, like a medical oncology program? Dr. John Glick: Well, I came to Penn, my first day. Person who recruited me was on sabbatical. I asked where my office was and there was no office. There was an exam room. There was a clinic for indigent patients which we scrubbed by hand. There was another office for patients who paid. Within two months, I had abolished that. We had one– I hate to use the word clinic, people still use the word clinic today, but one office that took care of all patients, irregardless of means.   I saw every oncology consult in the hospital for four years. But I had a mentor, not only Buz Cooper, but fortunately, Jonathan Rhoads was Chairman of Surgery, and he was also Chairman of the President's Cancer panel. And what he said at Penn in surgery became the law. And then when we introduced lumpectomy for breast cancer and radiotherapy, he endorsed it immediately. All the other surgeons followed suit. I don't think there's any hospital in the country that adopted lumpectomy and radiotherapy for breast cancer as quickly. And the surgeons were instrumental in my career.  Now, I was taking care of gliomas, head and neck cancers, and it was difficult. If I had a colorectal patient, I'd call Charles Moertel at Mayo Clinic and say, “What do I do?” I was there when Larry Einhorn in 1975 presented his data on testicular cancer with the platinum. Unbelievably inspiring, transformational. It also showed the importance of single-arm studies. You didn't have to do randomized studies because the results were so outstanding. And so in my career, I did both single-arm studies, proof of principle studies, and then many randomized trials through the cooperative groups.  But the first four years were very difficult. I didn't know what the word ‘work-life balance' meant in those days. If somebody was sick, I stayed and saw them. It was difficult introducing new principles. When I first mentioned platinum after Larry's presentation, I was laughed out of the room because this was a heavy metal. When patients were dying, they died in the hospital, and I wanted to hang up morphine to assist them. The nurses reported me to the administration. I had to fight to get the vending machines for cigarettes out of the hospital. So there were a lot of victories along the way and a lot of setbacks.  It took me several years to have an oncology unit of six beds, and now I think we have 150 or 160 beds and need more. So it was an interesting and, in retrospective, a wonderful experience, but I didn't know any better. Fortunately, I had a great wife who was working at Penn and then at Medical College of Pennsylvania, and she was incredibly understanding, never complained. And I think my kids knew that on Tuesdays and Thursdays, don't bring up anything difficult with dad because he's had a really tough day in clinic. Dave Johnson: We were not in that era, but we were very close. And many of the struggles that you had were beginning to dissipate by the time we were completing our training. But it was still a challenge. I mean, all those things. I gave my own chemotherapy for the first few years I was in practice. I don't know that our colleagues today who have trained in the last, say, 10 or 15 years, actually realize that that was what we did. Most of the chemo was given in the hospital. It was not uncommon in the early days to have 20, 30, 40 inpatients that you would round on because there just wasn't an outpatient facility. But the corporate mind made a big difference, allowing us to give drugs like platinum in the outpatient arena. You span all of that era, and so you've seen the whole panoply of change that has taken place.  John, the other thing you did that has impressed me, in part because of my time as a Chair of Medicine, is you created this Academy of Master Clinicians. Can you tell us a bit about that and what was the motivation behind that?  Dr. John Glick: Ben had a strategic plan, and one of the pillars was talking about valuing clinical medicine and clinical excellence. But there was no implementation plan. It was sort of just words and left in the air. And I was no longer director of the cancer center, and I realized we had a lot of awards for research, awards for education, and no awards for clinical excellence. So I created the idea of having an academy and master clinician spend six months talking to all constituencies, chairs of various departments, directors of centers to get a buy-in. Wrote a three-page white paper for the dean, who approved it immediately. And then, as typical at Penn, I raised all the money for it. I went to one of my patients who was an executive at Blue Cross. I said I need $500,000 to start this program. And then subsequently, I raised $4 million to endow it. Today, it is the highest honor that a Penn clinician can receive.  You could be on any one of our multiple tracks. You have to see patients at least 60% of the time. You not only have to be a great doctor, you have to be a humanist. So the world's best thoracic surgeon who has a demeanor in the operating room that is not conducive to working with a nurse as a team doesn't get in. We emphasize professionalism, mentorship, citizenship, teaching, national reputation, local reputation, and clinical excellence. And so we've elected over 100 people, maybe 3% of the Penn faculty. We give an honorarium. We have monthly meetings now by Zoom. We have monthly meetings on various topics. We never have a problem getting any dean or CEO to come talk to us.  We were the first to do Penn's professionalism statement. The school subsequently adopted, and it's become the highest honor for a Penn clinician. It's very competitive. It's peer-reviewed. The dean has no influence. And we're very proud that 40% of the members of the academy are women. We have a high percentage of diversity compared to the numbers on our faculty, but you really have to be elected on merit, and some people that you might expected to be members of the academy aren't. It's one of the things I'm proudest of. It will go on in perpetuity because of the money we've raised. I think many of my accomplishments as a researcher will fade, as they typically do, but I'm very proud of the Academy, and I'm very proud of the people that I've mentored. Dave Johnson: It speaks to your values, John, and I think it's one of the reasons why you're so widely admired. Thank you for creating that. It proved to be a model for other institutions. I know that for a fact. One would think that valuing clinical care would be preeminent in medical schools, but in fact, it's often ignored. So again, I know that your colleagues at Penn appreciate your efforts in that regard.  Tell us a little about your term as ASCO president. What are you most proud about and what were your most difficult challenges? Dr. John Glick: Well, the most difficult challenge was that ASCO was in transition. I had to fire the company that ran the meeting. We had to decide that ASCO was going to hire a CEO. We hired John Durant, made a small headquarters, tiny staff, and did a lot of the work as being chief operating officer myself. It was the year that email was just getting started, and ASCO wasn't using it. So every Saturday from 8:00 to 6:00, I came into the office and my secretary wrote letters inviting people to be on the program committee or various committees. But it was a society in transition. The growth of membership was huge. The meeting sites had to be changed. We emphasized science. Some of the things that we did are still in existence today.  We formed the ASCO ACR Clinical Research Methods course. It's still given. That's one of our real highlights. We forged relationships with other societies, the National Coalition for Survivorship. We made the ASCO guidelines much more prominent. And I remember that we were going to publish the first guidelines on genetic testing for breast cancer, and the MCI went up in absolute arms, so I arranged a meeting. I was at the head of the table. On my right were Francis Collins, Richard Klausner, Bob Wittes, and a few other people. Then the ASCO people who wrote the guideline were on the left, and they didn't want us to publish it. They thought it was premature to have a guideline about genetic testing. And what I learned from that meeting is that you can agree to disagree with even the most prominent people in oncology and still maintain those relationships. But we did what's right, and we published a guideline on the JCO. There were so many wonderful things that happened at ASCO that I can hardly restate all that happened I guess 27 years later. It was exciting. ASCO was still young. There was a lot we had to do, and we could do it. You could just go ahead and do it. It was exciting. It was gratifying. It was one of the most fun years of my life. Dave Johnson: I mean, that transition from an outside company in many respects, controlling the premier activity of ASCO, its annual meeting to ASCO, taking that on, that defined ASCO, and that's what I remember most about your time as president. It was a bold move, and the hiring of John Durant was brilliant. I mean, he was such an incredible individual, and it was great that you guys were able to pull that off. Pat Loehrer: Thank you for what you've done.  You've had a number of your mentees if you will, and colleagues that have gone on to prominent positions, including, I think, at least three directors of NCI Cancer Centers. Can you just talk briefly how you would describe your mentoring style because you've been so successful? Dr. John Glick: First, there are two aspects. One is when people come to you, and then when you go to people, you sense they're in need. The key aspect of mentoring is listening. Not talking, listening. Looking for the hidden meanings behind what they're saying, not telling them what to do, presenting options, perhaps giving them clues on how to weigh those options in pros and cons, being available for follow-up. Mentoring is never a one-time exercise. Not criticizing their decisions. You may disagree with their decision, but it's their decision, especially if they've considered it. Being proud of the mentee, being proud of their accomplishments, following them over the years. And when they've gotten in trouble or failed to get the job that they wanted, always be there for them, not just in the good times, but in the times that are difficult for them professionally. I think that's one of the most important things.  Even today, I mentor three or four clinical department chairmen, and people ranging from full professors to newly appointed assistant professors. Now that I'm retired, mentoring is the one activity that I've really retained. It's extraordinarily satisfying, and I'm proud of the people that I've mentored. But it's their accomplishments, and the key aspect of mentoring is never to take credit. Dave Johnson: I'll give you credit for mentoring me, and I appreciate it. You were very instrumental at a very decisive point in my career when the old Southeast Cancer Group disbanded, and we were looking for a new cooperative group home. And you were instrumental in helping my institution come into the ECOG fold, and not just as a very junior member, but really as a player. And I'll never forget that, and we'll always appreciate that very much. Pat Loehrer: Ditto on my side, too. Dave Johnson: John, you mentioned that you're retired. What do you like to do in your "free time” if you're not mentoring? Dr. John Glick: Life is good. My daughter says I have a disease, O-L-D. My grandson says, “He's not old; he's almost 80. Look how well he's done.” “Here's $20.” I'm having fun. We are fortunate to have homes in different places. We spend the summer up in the Thousand Islands on the St. Lawrence River, spring and fall down in Charleston, then lots of time in Philadelphia. We travel. I play golf poorly. I'm getting a chance to read history again, go back to one of my great loves. I'm with my children and grandchildren more. I lost my first wife. I've been remarried for about twelve years, and I'm enjoying every moment of that. I'm not bored, but I do wake up in the morning with no anxiety, no realization that I have to herd sheep or herd cats. I have no metrics, I have no RVUs,  not behind of the EMR.  Dave Johnson: You're making it sound too good, John.  Dr. John Glick: We're having fun. And I have not been bored. I've not been down in the dumps. Each day brings a different aspect. We see a lot more of our friends. I exercise. I deal with the health problems that people get when they get older, and I have plenty of those. Seeing doctors takes a lot of time, but I'm grateful that I'm having these few years of retirement. I'm one of the people who is most fortunate to have attained everything they wanted to do in their professional life, and now I'm trying to do some of the same in my personal life. Dave Johnson: John, Pat and I both love to read. We love history. You mentioned that you're reading some history. Is there a book that you've read recently that you might recommend to us? Dr. John Glick: “the Last of the Breed” {With the Old Breed} It's about a private in the Pacific campaign who was not a commissioned officer; it's just a grunt on the ground. It brings the horrors of the Pacific island campaigns to life. But there's a huge number of books, some historical fiction. I'm a great fan of Bernard Cornwell, who's written about the Medieval times, Azincourt, 1356. I'll read two or three books a week. I'm devoted to my Kindle. Dave Johnson: If you could go back in time and give your younger self a piece of advice, what would that advice be?   Dr. John Glick: Try and achieve more of a work-life balance. I didn't have any choice. If I didn't do the consult, it didn't get done. That's not the situation today. But I have a second piece of advice, don't treat medicine as a 9 to 5 job. If a patient is sick, stay with the patient. Give the patient your home or cell phone number. Remember, medicine is not just a profession, but it can be a calling. Too few of our physicians today regard medicine as a calling. And even if you're employed, as most of us are by an academic or other institution, do what's right for the patient, not just what's right for your timesheet or the EMR. Remember that the patient is at the center of all we do and that medicine is a calling for some people, as it was for me. Dave Johnson: Great advice, John. Great advice.  Well, I want to thank Dr. Glick for joining Pat and me. This has been a delight. You're one of our role models and heroes.  I want to thank all of our listeners of Oncology, Etc., which is an ASCO educational podcast where we will talk about oncology medicine and other topics. If you have an idea for a topic or a guest you'd like us to interview, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content of ASCO, please visit education.asco.org. Thanks again. Pat, before we go, I've got an important question for you. I've been trying to school you recently, and you've failed miserably. So I'm going to ask you, why is it that McDonald's doesn't serve escargot? Pat Loehrer: I can't do it. I don't know. I give up.  Dave Johnson: It's not fast food. Pat Loehrer: I like that. It's good.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

On this episode of the Scale Up Valley Podcast, Mike Dias speaks with Joerg Heuer, CEO & Founder at EcoG. Key Takeaways: EV charging solutions that grow your business. Disrupting a market with a founding team that comes from the corporate world. Challenges and opportunities of the EV charging market. Lessons Learned from expansion to the US. How to handle strategic and financial investors. The power of a purpose driven venture.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.07.536063v1?rss=1 Authors: Harvey, B. J., Olah, V. J., Aiani, L. M., Rosenberg, L. I., Pedersen, N. P. Abstract: Independent automated scoring of sleep-wake and seizures have recently been achieved; however, the combined scoring of both states has yet to be reported. Mouse models of epilepsy typically demonstrate an abnormal electroencephalographic (EEG) background with significant variability between mice, making combined scoring a more difficult classification problem for manual and automated scoring. Given the extensive EEG variability between epileptic mice, large group sizes are needed for most studies. As large datasets are unwieldy and impractical to score manually, automatic seizure and sleep-wake classification are warranted. To this end, we developed an accurate automated classifier of sleep-wake states, seizures, and the post-ictal state. Our benchmark was a classification accuracy at or above the 93% level of human inter-rater agreement. Given the failure of parametric scoring in the setting of altered baseline EEGs, we adopted a machine-learning approach. We created several multi-layer neural network architectures that were trained on human-scored training data from an extensive repository of continuous recordings of electrocorticogram (ECoG), left and right hippocampal local field potential (HPC-L and HPC-R), and electromyogram (EMG) in the murine intra-amygdala kainic acid model of medial temporal lobe epilepsy. We then compared different network models, finding a bidirectional long short-term memory (BiLSTM) design to show the best performance with validation and test portions of the dataset. The SWISC (sleep-wake and the ictal state classifier) achieved greater than 93% scoring accuracy in all categories for epileptic and non-epileptic mice. Classification performance was principally dependent on hippocampal signals and performed well without EMG. Additionally, performance is within desirable limits for recording montages featuring only ECoG channels, expanding its potential scope. This accurate classifier will allow for rapid combined sleep-wake and seizure scoring in mouse models of epilepsy and other neurologic diseases with varying EEG abnormalities, thereby facilitating rigorous experiments with larger numbers of mice. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Rick Greene, MD, discusses with Margaret Kemeny, MD, the results of a phase III randomized trial that evaluated the effect of perioperative fluorouracil on overall survival in for colon cancer. Dr. Kemeny is author of, "Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292)." Dr. Kemeny is director of New York's Cancer Center of Excellence at Queens Cancer Center of NYC Health+Hospitals/Queens and Professor of Surgery at at the Icahn School of Medicine at Mount Sinai. http://doi.org/10.1245/S10434-022-12705-8

Dr. Shannon Westin and her guests, Dr. Michael Atkins, Dr. Adil Daud, and Dr. Gary Schwartz, discuss a definitive work: The DREAMseq Trial. TRANSCRIPT The guests on this podcast episode have no disclosures to declare.     Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that gets in-depth on articles that have been published in the Journal of Clinical Oncology. And it is my great pleasure to be your host. I'm Shannon Westin, GYN oncology, and I serve as the social media editor for the Journal of Clinical Oncology.   Today, we're going to be discussing a very exciting article describing “The DREAMseq Trial—ECOG-ACRIN EA6134, Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma.” This article was published in the JCO on January 10th, 2023.   And I am joined today by the lead author, Dr. Michael Atkins, who is Deputy Director, Georgetown Lombardi University Hospital, and Scholl Professor and Vice Chair of Oncology at Georgetown University Medical Center. Welcome.   Dr. Michael Atkins: Thank you. Nice to be here.   Dr. Shannon Westin: In addition, we are also accompanied by two experts in the field, Dr. Adil Daud, Professor in the Department of Medicine at the University of California San Francisco, and Director of Melanoma Clinical Research at UCSF Helen Diller Family Comprehensive Cancer Center. Welcome, Dr. Daud.   Dr. Adil Daud: Hi, great to be here.   Dr. Shannon Westin: And with Dr. Daud is Dr. Gary Schwartz, the Division Chief of Hematology Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center in Columbia, New York. Thank you for being here.   Dr. Gary Schwartz: Delighted to be here.   Dr. Shannon Westin: So I'm surrounded by experts, and I'm very excited as a GYN oncologist to hear all of what you all have learned in melanoma because we're always excited to take that back into our field. So I think first, though, for those of us that aren't melanoma experts, Dr. Atkins, can you just level set for us and tell us what was the standard of care for melanoma when you began this study?   Dr. Michael Atkins: Sure. Well, first of all, this was a study for patients with BRAF V600 driver mutations in their melanoma, which represents about 50% of the patients with metastatic melanoma. And at the time the study was launched in 2015, two BRAF/MEK inhibitor combinations were FDA approved and shown to produce significant progression-free survival and overall survival benefits relative to BRAF inhibitor monotherapy. In addition, combination checkpoint inhibitor therapy with nivolumab and ipilimumab was shown to be superior to ipilimumab and, in particular in patients with BRAF-mutant melanoma, also to nivolumab monotherapy based on the results of the CheckMate 067 study, leading to its FDA approval. So we had these two regimens there that were approved. Of note, despite the many debates and attempts to garner real-world evidence at the time—the study actually reported out in 2021—marketing data showed that half of all patients in the US with metastatic BRAF-mutant melanoma were receiving BRAF/MEK inhibitors, and only one-quarter received nivo-ipi as initial therapy. So there remained a confusion throughout the course of the study as to which regimen was best in the US and around the world.   Dr. Shannon Westin: Tell me, what led to the current study? Was it really trying to drive at that very question?   Dr. Michael Atkins: These were the best treatment available at the time. And they really had changed melanoma patient outcomes in ways that we could have only dreamed about just five to 10 years prior, when median survival for patients with metastatic melanoma was six to nine months. Hence, the DREAMseq trial, this doublet, randomized evaluation of advanced melanoma sequencing, was really an apt acronym for the trial. But we had these two regimens of BRAF/MEK inhibitors tending to display the overall survival curve, while immunotherapy tended to raise the tail. And at the time the study was launched, it was really unclear which treatment was preferred in general or for particular subsets of patients. And given that patients would likely have the option to receive both approaches, was there a preferred sequence? So the DREAMseq trial was a launch to address these questions.   Dr. Gary Schwartz: I can echo Michael's statement about that. There was also—having been at the beginning of immunotherapy and targeted drug therapy, the transformation of cancer medicine in melanoma was extraordinary. Over a very short amount of time, we transformed a disease that's incurable to curable. And I don't think anybody, at least not in my lifetime, that ever think we'd ever see—or I'd see that type of transformation. But the debate in the community was what should be the first therapy. Should it be a targeted drug combination targeting RAF and MEK for BRAF-mutant melanoma, or should it be immunotherapy? And actually, there was a trend favoring immunotherapy, I think, at the time of the start of the study. It was actually an unresolved issue that many of us were continuing to debate up to the publication of this data, which certainly has now solidified the role of immunotherapy as a starting point for patients with BRAF-mutant melanoma.   Dr. Michael Atkins: Thanks, Gary.   Dr. Shannon Westin: I would love for you—because it is a complex design, and I feel like a lot of times, as drug developers, we're often discouraged to do too many lines in a row. And I was just so intrigued at how well this was laid out to really understand those very questions of superiority as well as sequence, which we don't often assess. Dr. Atkins, will you just summarize the design so that all of the very smart researchers on the line can utilize that for their own cancer types?   Dr. Michael Atkins: Yeah, it was complicated to execute, but the design was pretty simple. Patients with treatment-naive BRAF-mutant metastatic melanoma were stratified according to ECOG performance status and LDH normal and high and randomized in step 1 to receive either combination nivo-ipi induction for 12 weeks, followed by nivo monotherapy maintenance for up to 72 weeks—that was arm A, and that was standard of care for that regimen—or dabrafenib-trametinib continuously, and that was arm B. And if patients experienced disease progression and met the step 2 eligibility criteria, they were able to cross over to the alternative sequence: arm C, dabrafenib-trametinib, or arm D, nivo-ipi. And we followed the patients and chose two-year overall survival as the primary endpoint.   Dr. Shannon Westin: And we kind of got a little hint. So what was the primary finding?   Dr. Michael Atkins: Yes, because of the anticipated distinct shapes of the overall survival curves, with the BRAF/MEK inhibitors tending to have their benefit early and the immunotherapies tending to raise the tail of the curve, we thought there'd be non-proportional hazards and that the overall survival curves might cross. And therefore, we chose as a primary endpoint two-year landmark overall survival, with an estimate that the nivo-ipi first sequence would have a 70% overall survival rate compared to 50% for the dab-tram first sequence. And with 300 patients enrolled and 270 evaluable, there was about a 90% power to show this difference in two-year overall survival rate, with a two-sided type one error rate of 0.05.   Dr. Shannon Westin: And it met its primary endpoint?   Dr. Shannon Westin: Yes, the study was opened in July of 2015, and it was set up that there would be Data Safety Monitoring Committee meetings after the first 100 patients were accrued every six months and that the data cutoff used for the fourth interim Data Safety Monitoring Committee meeting, which was a median follow-up of a little over two years, 265 patients had enrolled in step 1—those were evenly split between the two arms—and 73 had enrolled in step 2, with nearly two-thirds of those being on arm D, second-line nivo/ipi. And the two initial arms were balanced for most of the characteristics and was randomized for the important characteristics.   And from an efficacy standpoint, once again, we chose landmark two-year overall survival as a primary endpoint. And the overall survival curves for the combined sequences showed the anticipated biphasic pattern; they actually crossed around 10 months, and 100 patients had died, with 62 of them on the sequence beginning with dab-tram. And the two-year overall survival rate was 72% for patients who started on nivo/ipi and 52% for those who started on dab-tram. And that was a pretty significant difference; P equals about 0.01 by log-rank test. And so this 95% repeated confidence intervals, along with the 20% difference in overall survival, ranged from 3% to 38%, and the O'Brien-Fleming boundary had been crossed based on this estimate. Interesting, as we published, the three-year overall survival difference was even greater, approaching 24%. So that was the main study endpoint. And because the Data Safety Monitoring Committee felt that that difference was clinically significant even though we had only had about 59% information, they recommended at that point that the study be closed early and that patients who were on arm B, dabrafenib-trametinib, be given the option to cross over to immunotherapy before disease progression.   So that was the primary endpoint. I'm going to pause there. There were some secondary endpoints that I think were interesting, but maybe Gary or Adil have comments about this.   Dr. Shannon Westin: I hope they do, yeah. I'm going to give over my podcast hosting to you.   Dr. Adil Daud: Mike, congratulations on that study. I mean, that's transformative. I mean, I think there was a feeling, like Gary was saying, that immunotherapy might be better in the long term. But I remember a lot of discussions, and I think you answered them in 2015 or 2014 and 2013 because you've been working on this design for a while, that the people who were treated with BRAF inhibitor therapy were just different. And a lot of people would say that when somebody walks into the clinic, the folks who are BRAF-mutant, they just have rapidly progressive disease, like something really bad is going on. And that's why the results on BRAF/MEK inhibitor therapy just looked different than immunotherapy. Immunotherapy was for slower-growing tumors, and I think your study kind of puts maybe a different spin on that, basically suggesting differently. Would you comment on that?   Dr. Michael Atkins: Yeah. So, Adil, I think early on, people thought that the BRAF/MEK inhibitor was for patients who had rapidly progressive disease, and you needed to get a response to get the disease under control. But over time, as those studies were followed out, it appeared that the BRAF/MEK inhibitors tended to work best in patients who had less aggressive disease—performance status 0, M1a or b disease, and normal LDH. And so it was still confusing as to who should get which therapies. And when you compared the results using retrospective data between those who got immunotherapy and those who got targeted therapy, it was really difficult to be sure that these were the same patient population. So the only way you could really know whether immunotherapy was truly better was to do prospectively randomized studies where the two arms were balanced, which is what we set out to do in DREAMseq.   Dr. Adil Daud: Yeah, I think there's a lot of areas in oncology where people think whether you should give somebody a CAR T-cell or whether you should give somebody myeloma therapy or—people think, well, these are just totally different. Or in melanoma, I think, the TIL therapy, there's this question about, can you really compare that to anything else? And I think your study, which perhaps wouldn't be done by a pharmaceutical company and perhaps wouldn't be— outside of the cooperative groups, I feel that it's hard to really do a study of that type.   Dr. Michael Atkins: I agree.   Dr. Gary Schwartz: Yeah. First, I want to say congratulations on really an extraordinary study, Michael. I think it really answers some critical clinical and biological questions that have been subject to debate in the melanoma and the medical oncology community for the last five or more years.   There were a couple of things that surprised me. One was the fact that patients that started on dab-trame, when crossed over to immunotherapy, the outcomes were pretty poor. And that was a biological outcome, I guess, we kind of thought about. But this study certainly suggests that there's something about prior targeted drug therapy that may affect outcome and immunotherapy. And also, the other thing that was surprising was the number of dropouts that developed and couldn't cross over because of the rapid progression on the first-line study. Do you want to comment on both of those points and maybe share some thoughts about what that means for the medical care of patients who get this type of treatment?   Dr. Michael Atkins: Sure. First of all, response rates were similar between the step 1 regimen and for dab-tram, whether used in step 1 or step 2. In contrast, as you said, nivo-ipi appeared to be less effective after progression on dab-tram than in the first line. It was like a 46% response rate in the first line, and about 30% in the second line. The median PFS in the first line was about 11+ months, and in the second line, was only about three months. And I think there was some feeling in the community—probably wishful thinking and also based on what I think are some flawed preclinical and translational studies—that BRAF/MEK inhibitors might cause some immunogenic cell death and cause new antigens to be expressed and activate the immune system, be synergistic with immunotherapy given afterwards, while I think other data suggested that the resistance mechanism to the dabrafenib-trametinib was immunosuppressive, leading to upregulation of VEGF and things like that.   So this result suggested that immunotherapy didn't work as well in the second line. There are probably several reasons for that. It could be biologic changes, which I think we don't pay enough attention to when we think about what we're doing in the first and the second line. But also the type of patients who progressed on BRAF/MEK inhibitors. when you stop those drugs, the disease tends to accelerate. Many of them probably had subclinical CNS disease, and it was just not a good time for them to be going on immunotherapy, while in the front line, you didn't have to deal with those type of issues. And with regard to crossover, one of the things that we looked at as a secondary endpoint in this study was feasibility of doing the crossover. Because in clinical practice, we found that if you waited until disease progression on BRAF/MEK inhibitors and then tried to cross them over, oftentimes, patients progressed really rapidly, and you weren't able to get the immunotherapy in to large degree, while in patients who got immunotherapy, they had a lot of toxicity often, which caused them to stop therapy. And if they had toxicity at the time they were progressing, it might be complicated to add new drugs in.   And so I think the community was a bit surprised that only about half the patients were able to successfully cross over. But I think that's reality, that if you use these drugs to progression and then have eligibility criteria, which you have to have in a clinical trial for patients to go on the second-line treatment, you're going to have a lot of dropouts. One of the major reasons for dropouts on dab-tram was progression in the CNS, and dabrafenib-trametinib doesn't work as well in the CNS as it does systemically, while immune therapy actually appears to work as well for patients with asymptomatic or undetected CNS metastases as it does systemically. And I think that was an important reason why immunotherapy was better.   Dr. Gary Schwartz: I've looked at your paper now multiple times, Michael, and I can't think of any reason why anybody would want to start a targeted therapy for BRAF-mutant melanoma. I mean, I think this really becomes a definitive study declaring that immunotherapy is where all medical oncology should begin in the treatment of BRAF metastatic melanoma. Is that too much of a statement to make, or would you agree with that as well? I've been trying to think of all the reasons why not to give immunotherapy first. I can't think of one now, after your paper, that would suggest otherwise.   Dr. Michael Atkins: Well, I've been chastened by a lot of reviewers, as you know, to say that these results only definitively apply to the patients who were eligible for this study. And patients who had poor performance status or active brain mets or who required steroids and needed to be in the hospital or had to have a response were not eligible for this study. And so I think there are some patients where the disease is just on fire, where you may need to give BRAF/MEK inhibitors to try to cool it off before you start immunotherapy, particularly if patients need to be on immunosuppressive drugs to control edema in their brain, or because of bone mets pressing on the spinal cord or things like that, I think that it's important to have that other option. But as soon as you can, as soon as you've created enough window to get patients off immunosuppressive drugs or improve their performance status enough so that they can be an outpatient, you probably should switch to immunotherapy and give them the chance for a long-term benefit.   Dr. Adil Daud: I have doctors call me outside of academia and say, “Hey, I've got a patient walking in. I'm trying to decide, should I do the triple therapy, or should I do…”—which triple therapy in melanoma refers to dabrafenib plus trametinib plus a PD-1 drug like pembrolizumab or, in some cases, like a PDL-1 inhibitor—and they're questioning whether that's an appropriate place to start. Or sometimes people say, “Well, what about doing a sandwich regimen where we start off with dabrafenib-trametinib and then switch over to something else without waiting for progression just to give people…” And I give a long-winded answer to that, but I'm curious to hear what you think, what you both think.   Dr. Michael Atkins: So my view is—I've always thought, based on some of our early translational studies, which were presented at ASCO and hopefully we'll be able to publish soon, that the BRAF/MEK inhibitor data that showed that there was an influx of immune cells and potential synergy was actually an artifact, that it was not increasing immune cells in the tumor microenvironment, but actually loss of tumor cell in the tumor microenvironment that was causing the impression that the tumors were more inflamed. And I felt that when it came to immunotherapy, BRAF/MEK inhibitors were not ipilimumab and were not going to add to the benefit that we see with immunotherapy of durable responses the way you can see with nivo/ipi.   So I've stayed away from those triplet regimens, and I think we've seen with the studies that have been published so far that they tend to have sub-additive benefit when you add an anti-PD-1 to BRAF/MEK inhibitors. You see some prolongation of PFS, but you don't see the same tail of the survival curve. And even at two years, the tail of the survival curve for those triple regimens is below where it is for nivo/ipi in the BRAF-mutant population all the way out at five years. And the nivo/ipi population—I'm talking about the progression-free survival curve—and that nivo/ipi population can still get BRAF/MEK inhibitors if they progress. So I think that triple regimen, I can't think of a patient where I would use that. But the sandwich regimen, as I was just describing, may be useful in some patients who just aren't in appropriate shape to start with immunotherapy.   Dr. Gary Schwartz: Now, I would agree with Michael. I think the clinical trial data would really discourage the use of triplet therapy. They really lean—again, the benefit of triplet therapy for all the published papers we've seen so far in that area. But I guess you're right. The idea, if you have one of those patients that comes in and who's really on fire with rapidly progressive disease, on steroids, and needs a very quick benefit, perhaps initiating targeted therapy first for a short time would be reasonable in the treatment of those patients. But beyond that, I really think there probably are not going to be many exceptions to starting immunotherapy first because your data, to me, strongly would suggest that starting targeted therapy is going to diminish the benefits of immunotherapy to follow. And that, to me, is an important take-home point of the study and sort of validates some of the preclinical data. I mean, depends what you look at. But there is preclinical data suggesting that MEK inhibition will diminish T-cell responsiveness, and I think this supports that biological effect. So I think we have to be cautious about upfront targeted drug therapy now and have to find what are those opportunities where it may be appropriate. But I think they're really diminishingly few.   Dr. Michael Atkins: And I would just emphasize the flip side of that, which is that targeted therapy is equally effective in the second line for patients who don't respond to immunotherapy. And I think that was also a critical component of why the immunotherapy first sequence was better than the targeted therapy first sequences. You had better salvage.   Dr. Gary Schwartz: That's a very good point.   Dr. Shannon Westin: Well, I personally just want to thank the three of you. I learned a ton today, and I fully intend to take that back to the work that we're doing in gynecologic malignancies, combining immune therapies and targeted therapies, and I hope our listeners will do the same.   Further, I agree with you, Dr. Schwartz. I think this is a practice-changing study. I appreciate you, Dr. Atkins, in being a little cautious. I appreciate the editors that reviewed it as well. But this is as clear a definitive trial as we can get and a testament to your hard work through the cooperative groups, which we all know can be a struggle in itself to get this type of trial through. So congratulations again.   Dr. Gary Schwartz: And I think the lessons learned in melanoma are going to be applicable to all solid tumors. So melanoma is about so far ahead of many other tumors, but what we learned here isn't just impacting melanoma, but will impact all cancer medicine. And I think that what's so important about this trial is that lessons learned here really are broadly based and have clinical applications to many patients getting immunotherapy, targeted drug therapies today. So congratulations, Dr. Atkins. I think you hit a home run on this one. The medical oncology community is indebted to you and to your group to making this possible. And thank you for bringing it to JCO as well. I think that itself speaks to the success of the journal and the impact these types of studies have on reaching a large segment of the medical oncology community.   Dr. Michael Atkins: Well, thank you very much, Gary. I do want to emphasize the point you made, that I think this result does impact how we think about the use of targeted therapies or chemotherapies or antiangiogenic therapies in other tumors in coordination with immunotherapy. And I'm sort of on a mission to make the point that if you want to get the most benefit out of immunotherapy, you should give it first, and you should give it unencumbered by other things that might interfere with its activity.   Dr. Gary Schwartz: I think that's the last word, Shannon.   Dr. Shannon Westin: I believe it is. I believe it is. Thank you all so much for being here. And thank you to our listeners for being here for another episode of JCO After Hours. Again, we were discussing “Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134,” published in January 10th, 2023, in the JCO.   Please do check out our other podcast offerings. You can check them out on the JCO website or anywhere you get your podcasts. Until next time, be well.     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.  

In this discussion, we cover her work on characterizing the variability of coherence as it relates to aging and how this coherence is increased by providing subject with ketones - an alternate source of energy to glucose. We then go into her work in modeling brain circuits and determining where the circuitry is altered across trajectories of disorders. In this context, we briefly discuss her work characterizing the effects on amygdala activation by different composition of inhaled perspiration - either that produced in a fear state vs that produced through exercise. Lastly, we discuss her lab's work on neuroblox - a simulation program for testing circuit models of the brain and how it may open up the diagnostic value of brain imaging data. Guest: Lily Mujica-Parodi, Ph.D. is Director of the Laboratory for Computational Neurodiagnostics (LCNeuro) at Stony Brook University. LCNeuro's research focuses on the application of control systems engineering and dynamical systems to human neuroimaging time series (fMRI, MEG, EEG, NIRS, ECOG), with neurodiagnostic applications to neurological and psychiatric disorders. One of LCNeuro's primary goals is to identify key points of failure in the regulation of neural control circuits which, depending upon how they break, lead to signs and symptoms that cluster as distinct psychiatric diagnoses. As a test case for this approach, her lab is working to understand how the prefrontal-limbic circuit “computes” potential threat in the face of incomplete sensory data, across a clinical spectrum that ranges from pathological fear (generalized anxiety disorder, phobia, post-traumatic stress disorder, paranoid schizophrenia) to recklessness. A second direction at LCNeuro considers fMRI connectivity as the solution to an optimization problem imposed, in part, by metabolic constraints at the mitochondrial scale. Her group uses biomimetic modeling to predict trajectories, based on biological “rules” of energy optimization, which are then validated against data. Experimentally, they expand and contract neurons' access to energy while observing consequent self-organization and re-organization of networks. The hope is that this work will have important implications for understanding brain aging; specifically, the epidemiologically observed impact of insulin resistance on cognitive decline.

The Landmarks in OncoPharm series returns to discuss adjuvant interferon in melanoma. ECOG 1684: https://pubmed.ncbi.nlm.nih.gov/?term=36649675 Commentary on E1684: https://ascopubs.org/doi/abs/10.1200/JCO.22.02354

JCO PO author Dr. Shilpa Gupta, MD, Associate Professor of Medicine at the Cleveland Clinic and GU Medical Oncology Director, shares analysis on outcomes in real-world settings for metastatic urothelial carcinoma (mUC) patients. Host Dr. Rafeh Naqash and Dr. Gupta discuss the utility of tumor mutational burden (TMB) to determine treatment, and mUC patient response from immune checkpoint inhibitors (ICPI) as compared with carboplatin. Click here to read the article!   TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations. I am Dr. Rafeh Naqash, assistant professor of medicine at OU Stephenson Cancer Center. You're listening to the JCO Precision Oncology Conversations podcast.   Today I'll be talking with Dr. Shilpa Gupta, who is an associate professor of medicine at the Cleveland Clinic and also the GU Medical Oncology Director. And we'll be talking about their group's recent paper, ‘Tumor Mutational Burden as a Predictor of First-Line Immune Checkpoint Inhibitor Versus Carboplatin Benefit in Cisplatin-Unfit Patients With Urothelial Carcinoma'.   Full disclosures for our guest can be found on the article's publication page.   Hello and welcome to the podcast, Dr. Gupta. It's nice to have you here. For the sake of this podcast, we'll be referring to each other using our first names. So welcome and thanks for joining us today.   Dr. Shilpa Gupta: It's my pleasure to be here, Rafeh, I'm really excited about chatting about this paper with you. Thank you for the opportunity.   Dr. Rafeh Naqash: Thank you so much. So today we'll be discussing this interesting publication of yours, talking about biomarkers. And I often refer to biomarkers as the Pandora's Box for immune checkpoint inhibitors because definitely one size does not fit all. And reading through your paper, I saw a lot of interesting findings that you have defined in this publication. But for starters, what was the premise and background of why you wanted to study this question of tumor mutational burden as a biomarker in this patient population?   Dr. Shilpa Gupta: Yeah, that's a great question, Rafeh. The treatment paradigm for urothelial cancer patients has really evolved over the last many years. For example, patients who are eligible to receive cisplatin-based chemotherapy, that's the treatment of choice. And for patients who are not eligible to receive cisplatin due to a variety of reasons like chronic kidney disease, heart failure, peripheral neuropathy, poor performance status, or hearing loss, in the past, we used to treat them with gemcitabine and carboplatin, but outcomes were quite dismal with median overall survival less than six months or so. And then in 2017, the approval of pembrolizumab and atezolizumab as single agents was welcome news because these patients had more durable responses and survival was longer than historically with gemcitabine-carboplatin. And this is what became the standard of care based on the FDA expedited approval.   However, in 2018, the FDA restricted the use of immunotherapy only to those patients whose tumors had high PD-L1 or who were not eligible to receive carboplatin, based on the interim analysis from the phase three trials IMvigor130, which compared atezolizumab to gemcitabine-carboplatin, one of the cohorts for cis-ineligible patients, and KEYNOTE-361, which compared pembrolizumab to gemcitabine-carboplatin in the cis-ineligible cohort. And furthermore, recently, the FDA actually further restricted the label for pembrolizumab, because in the phase 3 study, even in high PD-L1 subgroups, pembrolizumab did worse than gemcitabine-carboplatin, regardless of their PD-L1 status. There were early deaths, lower response rates, and in the IMvigor130 study, we recently saw that atezolizumab was actually withdrawn for this indication altogether.   So there has been this attraction for PD-L1 for a long time, but now multiple studies in urothelial cancer have shown that PD-L1 is not a durable biomarker. And we wanted to see if there's other biomarkers which can be accessible at the point of care. And we wanted to study how tumor mutational burden can or cannot pan out as a treatment selection or complementary to clinical criteria. Right now, there's no biomarkers to guide treatment for patients in urothelial cancer for carboplatin or immunotherapy use. And that was the premise for the study.   Dr. Rafeh Naqash: Excellent. Thank you so much for that detailed understanding of why you decided to pursue this.   Now, from the listener standpoint when you define cisplatin-ineligible patients, in your practice, what is the percentage of patients that you see who are technically cisplatin-ineligible? Does comorbidity play an important role in determining which patients, or does it depend on your discussion with the patient? What are those factors that you would describe to define what cisplatin-ineligibility would constitute?   Dr. Shilpa Gupta: So historically, Matt Galsky and colleagues described cisplatin-ineligibility as patients with a creatinine clearance less than 60 mLs per minute, hearing loss greater than grade two, poor ECOG performance status two or higher, peripheral neuropathy, which is significant or significant heart failure. Now, those all make patients ineligible for cisplatin. Now, more recently, we know that we can safely give cisplatin as long as creatinine clearance is above 50. So for the real world, 50 is a threshold where we can use split dose cisplatin. And I'll say, given that bladder cancer or urothelial cancer is a disease of the elderly, median age being 71 years, a lot of our patients have these comorbidities, chronic kidney disease, diabetes, and whatnot, which precludes us from using cisplatin. So in the real world, I would say that around 50% of patients are ineligible to receive cisplatin.   Dr. Rafeh Naqash: Interesting. And that goes back to the point where not everything that resulted from clinical trials, or the data that we get, may not be exactly applicable to the real world patient population, as you have pointed out in this interesting paper. So going back to the manuscript now from a methodology perspective, what kind of data did you include to get to the results that we'll talk about next? What was the inclusion and what was the patient population in this analysis?   Dr. Shilpa Gupta: So the patient population basically were patients who had a confirmed diagnosis of metastatic urothelial cancer. And the databases we used were the US-wide Flatiron Foundation Medicine Clinical Genomic Database, which has patients who were listed as metastatic urothelial cancer. But in addition, they also had genomic testing performed from their tumors, and results were available. And we accessed the database between 2011 until April 2021. And all these patients had had genomic testing using Foundation Medicine assay. And this de-identified data was basically US-wide across 280 cancer clinics and that's around 800 sites of care. And there's a whole range of retrospective longitudinal clinical data that was available, derived from the electronic health records comprising patient-level structured and unstructured data and also their genomic information from the tumors. And there was clinical data including demographics, lab values, performance status, timing of treatment, exposure, as well as time of progression and survival.   We decided to include patients if they received a frontline single agent immunotherapy, no matter what it was, whether pembrolizumab, atezolizumab, Nivolumab, durvalumab or avelumab, or a carboplatin-based chemotherapy. And just for the readers, this is a retrospective review. So we just used these selected patients who got in these therapies. We also required that these patients had tumor mutational burden information available through the tissue biopsy and patients who received chemotherapy and immunotherapy together were excluded and details are present in the manuscript, but this was pretty much the broad selection criteria.   Dr. Rafeh Naqash: Thank you so much. And definitely a very representative patient population from a real world setting with different therapy and different other clinical variables that are relevant in the real world setting.   So from an analysis standpoint, you, from what I read, define both a predictive and a prognostic aspect to tumor mutational burden. Could you tell us more about those results and highlight some of the interesting findings from that perspective?   Dr. Shilpa Gupta: Yes, absolutely. So as you know, tumor mutation burden cut off of ten mutations per megabase is currently utilized by the FDA, whereby approval of pembrolizumab for tumor agnostic condition was made. So that's what we considered high versus low. And we found that in this, after propensity weighing in, the tumor mutational burden less than ten group, basically those patients did not benefit from checkpoint inhibitor single agent as compared to tumor mutational burden of ten or greater. And so basically, we found that patients who had tumor mutational burden ten or higher overall had more favorable progression-free survival time to next treatment, as well as overall survival when they got a single agent immune checkpoint inhibitor, as opposed to those who got carboplatin, and also when compared to those who had tumor mutational burden less than ten. So we also looked at PD-L1 information available from the genomic database, but it was only available for around 35% of patients and still we were able to see that PD-L1 did not correlate with any of these outcomes as we show in the paper.   Dr. Rafeh Naqash: I see. And as you mentioned, you show both time to treatment failure PFS being better in TMB high patients defined as ten mutations per megabase. I didn't specifically see results related to TMB high versus low in a carboplatin specific cohort. Is that analysis something that was looked at and trying to understand whether neoantigens in a platinum-based setting specifically make a difference whether high TMB is predictive there in the carboplatin setting. Was that looked at?   Dr. Shilpa Gupta: So yes, we looked at, in the Figure 4, for the comparison of the TMB and which we were looking at the checkpoint inhibitor versus chemo. So for TMB low the chemotherapy cohort had more favorable results. Is this what you were getting at?   Dr. Rafeh Naqash: Yeah, I think what I was specifically trying to look at, like you have shown in the paper, is TMB is predictive of benefit with checkpoint inhibitors and is also prognostic in the checkpoint inhibitor setting. So my question was more whether it had a prognostic implication in a carboplatin specific cohort. So meaning high TMB, whether it correlated with better outcomes with carboplatin therapy versus low TMB. So if that was looked at.   Dr. Shilpa Gupta: We didn't look at that specifically, we only compared whether high TMB did better with the immunotherapy or chemotherapy.   Dr. Rafeh Naqash: And some of the correlation of this in my mind comes from some data that people have looked at in the lung cancer setting, whether high TMB makes a difference and for example, resected lung cancer patients, which usually gets platinum-based adjuvant therapies. So that's why I was wondering if there's any correlation there. But this is definitely interesting.   Now, my next question was going to be in your manuscript you mentioned around 30% of patients had tumor mutational burden more than or equal to ten. Did you identify any other unique characteristics from any other mutational standpoint or a PD-L1 standpoint in the high TMB cohort?   Dr. Shilpa Gupta: Yes. So PD-L1 didn't really stand out to be a very steady biomarker in our experience. And this is also what was reflected in the phase three trials like DANUBE where they looked at the durvalumab and tremelimumab, IMvigor130 or KEYNOTE-361. So that was pretty consistent that these studies also showed TMB to be more useful in exploratory analysis. Of course, these patients were not stratified based on that. And we also looked at other emerging biomarkers, for example, F-TBRS and angiogenesis gene expression signatures as well as tGE3. And we need to evaluate them in a separate study to see what pans out.   But for now, I think as far as in the real world, we are looking at a lot of genomic testing being done and right now we really don't know how to use that for making treatment decisions, right? PD-L1 has really phased out as of any utility whatsoever. And using TMB; I think in addition to the clinical characteristics, like when possible, we should be offering patients carboplatin. There's no doubt about that for cisplatin ineligible patients. But there's those patients who, if they're refusing chemotherapy and we really can't make a case for giving them single agent immunotherapy, I think TMB can come in handy to justify and make sure that we're not doing them a disservice by not giving carboplatin. And I think future trials need to use this biomarker in a prospective setting to further establish its utility.   Dr. Rafeh Naqash: Definitely, I agree it's a case-by-case situation from a patient standpoint to determine what therapy is appropriate for the patient and what is most realistic, what is the expectation that the patient has, from that treatment.   Now, from a TMB standpoint, one of the ongoing debates is if it is a binary cut off or whether it could be tertiles for a certain tumor type or quartiles. Was there any subanalysis or any subsequent study that your team would be looking at from a TMB cut off standpoint? Maybe a higher cut off would mean a better outcome and maybe lesser duration of therapy in those patients. Is that somewhat of a consideration?   Dr. Shilpa Gupta: Yeah, that's a great question, Rafeh. And I think the reason we stuck to it as a binary end point is because that's the FDA definition, so people don't try to extrapolate based on anything higher or lower. But yeah, that's a great question. And I know in lung cancer they're looking at different ranges. As far as urothelial cancer, we just stuck to the ten mutations per megabase for now.   Dr. Rafeh Naqash: Of course. And one of the other interesting things I really like to see in the paper is your figure specifically on the ECOG performance status and how clinical trials sometimes do not include patients on the higher ECOG performance status spectrum. And your study obviously had a good representation on that standpoint. What were some of the findings from the ECOG standpoint that were somewhat different in your cohort than what you would see in clinical trials in general?   Dr. Shilpa Gupta: Yes, as we've shown in Figure 5, the ECOG in real world, it was quite an eye opener to see that there was a considerable number of patients who were documented as ECOG performance status three. And if you see the ECOG performance status two bar was around 50% and ECOG performance status one was also lower than what has traditionally been included in the phase three trials. And in the phase three trials, there's hardly any patients with ECOG performance status two compared to what we saw in the real world. And very few patients, in fact, hardly any had ECOG performance status zero in our real world analysis. So clearly the trials need to be more inclusive, as has been the ASCO message all along. And it's always very surprising to see the big gap between the real world and the clinical trial patient population.   Dr. Rafeh Naqash: Definitely, I think more and more, especially cooperative group trials that you and many others are leading, are trying to be as inclusive as possible, which is important to get a better understanding of how these therapies do in different patient populations. And one of the questions I wanted to ask you, and I've seen this a few times in different checkpoint therapy treated tumors, is this initial rapid progression in some patients where the chemotherapy arm does better, but the immunotherapy arm kind of falls rapidly and then starts plateauing. In your clinical experience, have you seen that? And if yes, what are the features of some of those patients that have this rapid progression from a clinical and both from a biomarker standpoint?   Dr. Shilpa Gupta: That's a great question, Rafeh, and we do see that every now and then, and especially in my experience, we've seen that in women in particular who have bone metastases are really challenging to treat with immunotherapy. And sometimes we find that the disease just rapidly blows through immunotherapy and we really need to do more biomarker work to understand what determines these biomarkers of hyper-progression, so to speak. I know there's a lot of work going on in the field and we are also trying to understand these by serially collecting blood and circulating tumor DNA from our patients during their treatment journey.   Dr. Rafeh Naqash: Exactly. Definitely work in progress and another unique patient population where more needs to be done to understand what are the events that lead to these hyper-progression aspects, whether it's in the bone or brain or any other compartment in the body.   Well, this has been exciting and interesting, but before we end, we try to know a little bit more about the investigator, the author. So, Shilpa, can you tell us a little bit about your journey in oncology and your journey as a trainee, your journey as faculty, as a clinical trialist, as a successful clinical trialist? And any advice for junior investigators listening to this conversation?   Dr. Shilpa Gupta: Yeah, thank you for asking. I think oncology always struck me as a very exciting field back in my residency days, 2005, 2006. And at the time, so much was going on, like just drugs like bevasizumab were just coming around for colorectal cancer and in lung cancer drugs like EGFR inhibitors were coming around. And that kind of really excited me. And talking with my mentor at the time, who was a really well-renowned transplanter, he said to me that if he had to do it all over again, he would love to get into solid tumor oncology with all the excitement that's going on. I was drawn to oncology also because of, not only it's a learning experience every day, but it can be very gratifying to see amazing responses and patients living longer despite having advanced disease, and also provides a lot of challenges every day when every patient is not the same. So I think that was the reason why I was drawn to oncology and provides us an opportunity to really develop new therapies as opposed to some of the other specialties because of how challenging the patient population is.   And as far as my journey, you know, I've now been in the US for almost 18 years and have been in a variety of places, and I think it's been a very rewarding journey despite multiple bumps along the way. And I'm really glad to be doing what I'm doing and trying to advance the field, clinical trials, and learning from people around me.   Dr. Rafeh Naqash: Thank you so much for giving us a little glimpse into your journey and your experiences. And it's always inspiring to listen to successful investigators and also try to emulate in some ways what you have done and what you've achieved. And thank you again for coming on this podcast. And thank you for choosing JCO Precision Oncology as a destination for your manuscript, and hopefully we'll see more of the same from you and your group in the subsequent years to come and more in this field of biomarkers.   Thank you for listening to JCO Precision Oncology Conversations. You can find all our shows, including this one, at ASCO.org/podcasts or wherever you get your podcasts. To stay up to date, be sure to follow and share JCO PO content on Twitter @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journal/PO.     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.     Guest Bio Shilpa Gupta, MD, is Associate Professor of Medicine at the Cleveland Clinic and GU Medical Oncology Director.   Guest disclosures Stock and Other Ownership Interests: Nektar, Moderna Therapeutics Honoraria: Bristol Myers Squibb Consulting or Advisory Role: Gilead Sciences, Guardant Health, AVEO, EMD Serono, Pfizer, Merck, Loxo/Lilly Speakers' Bureau: Bristol Myers Squib

In der Mittagsfolge begrüßen wir heute Jörg Heuer, CEO und Co-Founder von EcoG, und sprechen mit ihm über die erfolgreich abgeschlossene Series-A-Finanzierungsrunde in Höhe von 6 Millionen Euro.EcoG ermöglicht Ladestationsherstellern, DC-Ladestationen schnell und kostengünstig zu entwickeln. Die Ladetechnologie- und Betriebssystemlösung kann modular als Hardware- oder reine Software-Lösung eingesetzt werden, um DC-Ladegeräte jeder Art zu entwickeln und zu betreiben. So soll das Ladenetz für Elektrofahrzeuge mit Technologien ausgestattet werden, die ein schnelles Wachstum der Ladeinfrastruktur ermöglichen und zu einer emissionsfreien Mobilität beitragen. EcoG wurde im Jahr 2017 von Johannes Hund, Jörg Heuer und Manuel Heckmann in Oberhaching gegründet. Über 15 verschiedene Hersteller setzen bereits auf die Lösung bei mehr als 24 verschiedenen Ladegeräteserien. Das EcoG-Ökosystem umfasst mittlerweile mehr als 50 Partner, die vielfältige Möglichkeiten zur individuellen Produktimplementierung bieten. Innerhalb von etwas mehr als zwei Jahren hat das Startup nach eigenen Angaben einen Marktanteil von 10% in Europa erreicht. Zuletzt konnte EcoG seinen Quartalsumsatz vervierfachen und hat damit bereits die Profitabilität erreicht.Nun hat das Münchner Startup 6 Millionen Euro in einer Series A eingesammelt. BayBG und Lindner Group unterstützen die Runde als neue Investoren. Die bestehenden Kapitalgeber Ananda Impact Ventures und Helen Ventures haben sich ebenfalls erneut beteiligt. Das frische Kapital soll zur Skalierung, zum Wachstum und zur Internationalisierung eingesetzt werden.

In der Rubrik “Investments & Exits” begrüßen wir heute Jan Miczaika, Partner bei HV Capital. Jan hat den Exit von Vimcar und die Runde von EcoG und Variolytics kommentiert:Battery Ventures, ein amerikanischer Private Equity-Investor, hat das Berliner Startup Vimcar für 135 Millionen Euro übernommen. Vimcar ist ein Connected Car- und Fleet Management-Unternehmen, das 2013 von Andreas Schneider, Christian Siewek und Lukas Weber gegründet wurde und Fahrzeuge herstellerübergreifend vernetzt und Firmenwagen digitalisiert. In den letzten Jahren haben Investoren wie Acton Capital, Coparion, UVC Partners und Atlantic Labs insgesamt 18 Millionen Euro in Vimcar investiert. Bei der letzten Finanzierungsrunde im Jahr 2019 wurde Vimcar mit einem Wert von 45 Millionen Euro bewertet. Das Münchner E-Mobilitäts-Startup EcoG hat eine sechs Millionen Euro schwere Series-A-Finanzierungsrunde abgeschlossen. Neu an Bord sind die Investoren BayBG und Lindner Group, während die bestehenden Investoren Ananda Impact Ventures und Helen Ventures ihre Beteiligung aufstocken. Mit der Finanzierung möchte EcoG seine Marktpräsenz in den USA ausbauen und seinen Kunden bei der Skalierung der Produktion von DC-Ladestationen helfen. EcoG entwickelt Betriebssoftware für DC-Ladestationen und hat nach eigenen Angaben in etwas mehr als zwei Jahren einen Marktanteil von zehn Prozent in Europa erreicht. Das Stuttgarter Startup Variolytics, das sich auf die Vermeidung von Treibhausgasen in der Abwasseraufbereitung an Kläranlagen spezialisiert hat, hat eine siebenstellige Seed-Finanzierung erhalten. Die Finanzierungsrunde umfasst den High-Tech Gründerfonds (HTGF), FTTF und Dr. Jörg Gebhardt sowie weitere Angel Investoren. Variolytics hat eine patentierte Messtechnik und KI-basierte Prozesssteuerung entwickelt, die in Kläranlagen zur Erreichung ihrer Klimaziele eingesetzt werden kann. Das Unternehmen testet derzeit sein Produkt in Pilotprojekten in England und Stuttgart. Das Kapital aus der Seed-Finanzierung soll 2023 für eine Produktion genutzt werden, um Kunden in ganz Europa die Technologie anbieten zu können.

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC without driver alterations. He reviews the new evidence identified by the panel along with the updated recommendation regarding the role of bevacizumab in pemetrexed maintenance therapy. Dr. Owen also discusses exciting trials the panel is looking forward to seeing results of to drive future updates to the living guidelines. Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Dwight Owen, from Ohio State University in Columbus, Ohio, lead author on, 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, version 2022.2.' Thank you for being here, Dr. Owen. Dr. Dwight Owen: Thanks very much, Brittany, for having me. Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Owen, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Dwight Owen: I have research funding to my institution to conduct clinical trials from several companies, including Merck, Pfizer, Genentech, BMS, and Palobiofarma, but no ownership, no stock, and no employment history. Brittany Harvey: Okay, Thank you for those disclosures. Then let's get into the content of this living guideline update. So, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations. What new evidence was identified by the routine literature searches to prompt an update to the guideline? Dr. Dwight Owen: Yeah, so this is a really exciting time for patients with stage IV non-small cell lung cancer. We are anxiously awaiting the results of some ongoing immunotherapy combination studies. However, for this update, we focused on a specific paper and study that evaluated a treatment that is not our first option anymore, but maybe the first option for a subset of patients. So, before the standard introduction of immunotherapy for patients with stage IV non-small cell lung cancer, we often offered platinum-based doublet chemotherapy, and for years, we studied ways to make that better. So, we might introduce maintenance therapy where we continue a treatment after the first line of induction chemotherapy. We did either continuation maintenance, which is where you continue a treatment that seemed to be effective, or switch maintenance, where you were introduced to new therapy. For many folks with non-squamous non-small cell lung cancer, the standard treatment options included carboplatin or cisplatin with pemetrexed, which is an antifolate chemotherapy, or carboplatin and paclitaxel with or without a VEGF inhibitor, such as bevacizumab. One of the big questions was whether there was a benefit for continuing maintenance therapy with something besides pemetrexed, in this case, bevacizumab, and if bevacizumab was given in combination with pemetrexed, whether continuing that as a maintenance would offer benefit. Now, it's important to point out that the current FDA approval, at least in the United States, is for bevacizumab to be given with carboplatin and paclitaxel. However, several studies looked at the combination with pemetrexed and there were several issues with those studies. So, in one study they used a different agent, so ramucirumab instead of bevacizumab, both VEGF, but slightly different. In one study, the combination that was compared of pemetrexed plus bevacizumab was only compared to bevacizumab maintenance. And so, we really had a sort of hodgepodge of different trials that never answered the question of whether bevacizumab or VEGF therapy, given as maintenance offered any benefit to our patients. What Dr. Garon and co-authors did in a study that we evaluated was conduct a meta-analysis of four of those randomized trials, focusing on the question of comparing pemetrexed maintenance therapy alone versus in combination with bevacizumab. And what they found is that there was no significant difference in overall survival with the addition of bevacizumab compared to pemetrexed by itself, and there were higher rates of toxicity in those patients, including serious and higher-grade toxicities. So, I felt that it was really important to point out that the addition of bevacizumab or other VEGF therapies does not seem to add to a survival benefit when given as maintenance. And even though this is a subset of patients who perhaps could not get immunotherapy as a first-line treatment, maybe because of a pre-existing autoimmune disorder, but for those patients, it doesn't seem that the addition of VEGF as maintenance offers what we were hoping for. Brittany Harvey: Understood, and I appreciate you laying out the landscape of the data in this area. So then, based off this new data and the meta-analysis that you just described, what is the updated recommendation from the expert panel? Dr. Dwight Owen: So, the updated recommendation is a tweak to the established recommendation, which is essentially that for patients who are not candidates for immunotherapy for any reason, that platinum doublet chemotherapy is really the mainstay, and that if maintenance is offered, that it should not include VEGF therapy in combination with pemetrexed as compared to pemetrexed by itself. Brittany Harvey: Understood. And then, what should clinicians know as they implement this updated recommendation? Dr. Dwight Owen: I think, again, this should be a relatively uncommon scenario. Most of our patients are candidates for immune therapy. Many patients are offered platinum pemetrexed by itself. But when thinking about continuing maintenance therapy, we would recommend that most clinicians avoid the addition of therapies that haven't seemed to offer a survival benefit and incur higher rates of toxicity. Brittany Harvey: Great. That's helpful to know. And then you've just mentioned that this doesn't apply to a lot of patients, but what does this change mean for patients with stage IV non-small cell lung cancer without driver alterations? Dr. Dwight Owen: I think, hopefully, for the subset of patients where we're really thinking about here that we can at least avoid additional toxicity if there isn't a trade-off in terms of benefit, in terms of survival. Brittany Harvey: Great. Definitely, that's helpful. And then finally, what ongoing research is the panel keeping an eye on for future living guideline updates? Dr. Dwight Owen: So, there are a lot of exciting trials that are ongoing, and hopefully, we'll be able to read out soon, that would offer us updates for really how to manage these patients in the frontline setting with stage IV non-small cell lung cancer. We have multiple options now. This discussion that we've had today really focuses on the pre-immunotherapy era, but of course, bevacizumab is utilized in a regimen along with carboplatin, paclitaxel, and atezolizumab, compared to monotherapy with checkpoint inhibitors compared to chemoimmunotherapy and dual checkpoint inhibitors. And we don't really have any head-to-head trials yet, or strategies on how to identify which patients need more aggressive combination therapies versus which patients could potentially do without chemotherapy, or with single-agent checkpoint inhibitor by itself. So, while we wait for those studies like the ECOG and Cigna study, we're really looking forward to having those to be able to help decide and tailor our treatment options for our patients. Brittany Harvey: Great. Well, we'll look forward to the ongoing review of the literature by the panel and any future guideline updates to recommendations in the meantime. So, thank you so much for your work on this update and thank you for your time today, Dr. Owen. Dr. Dwight Owen: Thanks for having me. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's also a companion living guideline update on Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations, available there and in the JCO. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes, or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   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.  

Seminal Trial Series: ECOG 1594 by IASLC

Featuring an interview with Prof Axel Hauschild, including the following topics: Pan-tumor approval of dabrafenib/trametinib; data with adjuvant targeted therapy for melanoma (0:00) Emerging data with encorafenib/binimetinib for Stage II melanoma; switching from dabrafenib/trametinib to encorafenib/binimetinib (5:23) Recent data with ipilimumab/nivolumab versus dabrafenib/trametinib from the DREAMseq trial; using targeted therapy after immunotherapy (9:58) Relationship between tumor mutational burden and response to targeted therapies and immunotherapies; PD-L1 expression and efficacy of immunotherapy alone compared to in combination (15:36) T-cell targets for immunoregulatory antibody therapy; treatment for patients with underlying autoimmune disease (20:23) Influence of corticosteroids on immunotherapy efficacy; adverse event profiles of dabrafenib/trametinib and encorafenib/binimetinib and optimal management (25:13) Case: A man in his early 50s with an ulcerated melanoma metastasis and BRAF mutation (32:05) Case: A woman in her early 40s with BRAF-mutated melanoma and a poor ECOG performance status (41:25) CME information and select publications

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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. Guests' statements on this 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, 4 Cancer.Net Specialty Editors discuss new research in prostate, bladder, kidney, and testicular cancers presented at the 2022 Genitourinary Cancers Symposium and 2022 ASCO Annual Meeting. This episode has been adapted from the recording of a live Cancer.Net webinar held June 15th, 2022, led by Dr. Neeraj Agarwal, Dr. Timothy Gilligan, Dr. Petros Grivas, and Dr. Tian Zhang. Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah. Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig (TOSS-ig) Cancer Center. Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine. He is also an associate member of the clinical research division at the Fred Hutchinson Cancer Research Center. Dr. Zhang is an Associate Professor of Internal Medicine at UT Southwestern Medical Center and a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center. Full disclosures for Dr. Agarwal, Dr. Gilligan, Dr. Grivas, and Dr. Zhang are available at Cancer.Net. Greg Guthrie: Good afternoon, everyone. I'm Greg Guthrie, and I'm a member of the Cancer.Net content team. I'll be your host for today's Research Round Up webinar focusing on cancers of the genitourinary tract. Cancer.Net is the patient information website of the American Society of Clinical Oncology, known as ASCO. So today, we'll be addressing research from 2 2022 scientific meetings, the ASCO Annual Meeting held in Chicago in June and the Genitourinary Cancers Symposium held in San Francisco in February. Our participants today are all Specialty Editors of the Cancer.Net Editorial Board, and they are Dr. Neeraj Agarwal of the Huntsman Cancer Institute in University of Utah, Dr. Timothy Gilligan of the Cleveland Clinic Taussig Cancer Center, Dr. Petros Grivas of the Fred Hutchinson Cancer Research Center and University of Washington, and Dr. Tian Zhang of the University of Texas Southwestern Medical Center. Thank you, everyone, for joining us today. So starting us off today is Dr. Agarwal who will be talking about research in prostate cancer. Go ahead, Dr. Agarwal. Dr. Agarwal: Hi. Thank you, Greg. So I'd like to start with 2 studies. They both are in prostate cancer which will be followed by my colleagues presenting studies in other cancers in bladder cancer and kidney cancer. So I'll start with this abstract, which was highly discussed by the doctors at the ASCO Annual Meeting a few weeks ago, and it has a lot of relevance in our practice. So this is abstract #5000 presented by Dr. Michael Hofman, and this was the update on a clinical trial which compared lutetium PSMA-617, or lutetium PSMA, to put it simply, with cabazitaxel in patients with metastatic castration-resistant prostate cancer who had disease progression after receiving docetaxel chemotherapy. So, who were the patients who were enrolled on the study? These patients had, as I said, metastatic castration-resistant prostate cancer, who had disease progression after docetaxel chemotherapy, and who had to have high PSMA-expressing prostate cancer. And the way they assessed the presence of high PSMA expression was by using a specialized kind of PET scan known as Gallium 68 PSMA-11 PET scan. In addition, they made sure that these patients do not have another type of prostate cancer, also call it dedifferentiated prostate cancer, by making sure that those patients did not have a traditional PET scan-positive disease. So this was a highly selected patient population who were expressing PSMA on their prostate cancer. Prior to this presentation, the earlier presentation had shown that lutetium PSMA was superior to cabazitaxel as far as progression-free survival is concerned and also was associated with lower incidence of grade 3 or 4 side effects. In this update, after a longer follow-up of 3 years, Dr. Hofman and Dr. Davis, who is a senior author, they presented the data on overall survival, which was a secondary analysis, and overall survival was similar with cabazitaxel as well as lutetium PSMA in the range of 19 months. We did not see any new safety signal. So, what does it mean for us? What does this mean for our patients? My key takeaway message here is, lutetium PSMA is a suitable option for men with metastatic castrate-resistant prostate cancer who are expressing high PSMA on their prostate cancer after they had sustained disease progression after docetaxel. However, cabazitaxel is also a valid option in this setting. I would like to add my own view in addition to this because lutetium PSMA was better tolerated and was also associated with better progression-free survival. In my patients who are progressing on docetaxel chemotherapy, I would like to use lutetium PSMA first followed by cabazitaxel chemotherapy. So that would be my key takeaway from this abstract. Now we can move to the next abstract. This was also an update, a much longer update, on ENZAMET trial. If you recall, ENZAMET trial was one of those trials which established that deeper androgen blockade, or deeper androgen signaling inhibitors such as enzalutamide, apalutamide, or abiraterone, these trials were conducted in 2015 onwards, and all these trials showed that upfront using deeper androgen signaling inhibitors at the time of metastatic hormone-sensitive prostate cancer onset improved survival. So ENZAMET trial used enzalutamide, and it showed in the first analysis, which was presented by Dr. Davis and Dr. Sweeney in the 2019 ASCO Meeting Plenary session, that adding enzalutamide to androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer significantly improved survival. In this longer follow-up of 68 months, so we are talking about almost 6 years of follow-up, now, these investigators from ENZAMET trial, as presented by Dr. Davis, showed that the combination of enzalutamide with androgen deprivation therapy or testosterone suppression therapy continues to significantly improve survival in patients with newly diagnosed hormone-sensitive prostate cancer or metastatic prostate cancer. One interesting part of this unique aspect of this trial was that patients were allowed to receive docetaxel chemotherapy concurrently to the protocol treatment. And in this trial, 45% patients actually receive docetaxel chemotherapy. So 503 patients exactly out of 1,000-plus patients. So if you look at the subgroup analysis of those patients who received docetaxel chemotherapy, enzalutamide does not seem to benefit those patients from the overall survival perspective. So on the face of it, it looks like enzalutamide is not helping those patients who are receiving docetaxel concurrently. But there are some caveats with that kind of subgroup analysis. The first one is this is not a randomized assignment of docetaxel chemotherapy. Patients were determined to have docetaxel chemotherapy after discussion with their respective oncologist. This was not a prespecified analysis that so many patients with docetaxel will receive enzalutamide. Also, this was not a randomized assignment of docetaxel. And third, that I don't think this trial had enough power to look for that subgroup analysis. So my take on this trial is that updated results from this trial, almost 6 years of follow-up now show that enzalutamide continues to improve overall survival with a 30% reduction in risk of death in patients with metastatic castration-sensitive or hormone-sensitive prostate cancer. Furthermore, the effect of enzalutamide, in my view, on overall survival is independent of the receipt of docetaxel. If you look at the whole trial population for which the trial was covered for, enzalutamide improved survival for all patients. And based on these results, I feel more confident in saying that upfront intensification of treatment with deeper androgen inhibition remains a standard of care for our patients with metastatic hormone-sensitive prostate cancer and should be offered to all eligible patients with this condition. With that, I would like to wrap up the prostate cancer abstracts. Thank you very much. Greg Guthrie: And thank you, Dr. Agarwal. Next up, we will have Dr. Gilligan, who is going to be discussing testicular cancer. Dr. Gilligan: Thank you very much. So I have 2 studies I want to talk about and then just give a headline of some interesting things that I think are kind of coming down the road. Both of these abstracts have to do with improvement over time in specific patient populations we used to worry about. I'm not saying we don't worry about them anymore, but things are looking better now than they had 1 or 2 decades ago. So the first topic addresses late relapses in testicular cancer. And historically, we have been concerned that these patients did worse and had worse outcomes. And late relapse could variously be described as after 2 years or after 5 years. In the current study, they defined late relapse as being after 2 years and very late relapse as being after 5 years. And what was special about the study was that it captured the entire population of patients with testis cancer in Norway and Sweden so that it wasn't based on a center of excellence that gets selective referrals. It was actually a population-based study. And the key conclusion of the study was one I found, once again, that late relapses are rare. So for stage I patients, 2% of patients will relapse after 2 years, 1% after 5 years, and 0.5%, so 5 out of 1,000 patients, after 10 years. So if you're 2 years out, the likelihood of a relapse is quite low. And if you're 5 years out, it's half of that. In patients with metastatic disease, similarly, 3.6% relapse after 2 years, 1.6% after 5, and 0.8% after 10 years. And what was interesting to me was that if you looked at the more recent patients who were diagnosed after 1995 - I know that doesn't sound very recent, but they had even earlier patients also in the study - the very late relapse rate almost resolved and went away. It went from 2.2% all the way down to 0.8%. So I think with modern imaging, modern care patterns, we're seeing less of this than we used to. But overall, patients were doing better even if they do relapse late. One thing that was interesting in the study to me also was for stage I disease, we typically recommend surveillance rather than active treatment. So active treatment with non-seminomas would be a retroperitoneal lymph node dissection or more surgery or chemotherapy. With seminoma, it would usually be chemotherapy or radiation, although surgery is being investigated there now. And they did find that in men who chose surveillance, which we still recommend, the late relapse rate was a little bit higher, but it was still affecting a small percent of patients. So the relapse rate beyond 2 years was 4% rather than 1%, but out of 4,000 patients, there were only 3 deaths from late relapse. So this isn't changing the recommendation for surveillance, but it is an alert that patients who are on surveillance for stage I disease have a slightly higher risk of late relapse and that may affect how we follow them and specifically how long we follow them. One of the things that was interesting in the study is in the United States, we often stop scans at 5 years, but in the SWENOTECA countries, they continue scans all the way out to 10 years. I don't know that U.S. guidelines are going to change, but it was a provocative finding. The key thing, as I alluded to at the beginning, was that 61% of patients with late relapse were alive 10 years later, and while we would like that number to be higher, it used to be around 50% in older studies. So it's a significant improvement from where we were before. A particularly interesting thing to me was that patients relapsing 2 to 5 years out actually had the best prognosis. Patients who relapsed in years 1 to 2 had a worse prognosis and patients relapsing after 5 years had a worse prognosis, whereas the patients relapsing 2 to 5 years had a better prognosis. In the end, I think what this means for us is that patients are doing better. It's not going to really change our treatment patterns, but it's reassuring that we shouldn't be pessimistic about late relapses, and we still have a solid chance of curing them. So again, bottom line, most men with late relapse is cured and late relapse is less common now than it was earlier, particularly in non-seminomas. Let's go to the next study. So this is a different group of patients who had a particularly ominous prognosis historically and still we have a lot of room for improvement. These are patients with non-seminomas that start in the mediastinum. So in the chest, under the breastbone, under the sternum typically. And patients are treated aggressively upfront, they are considered poor risk at the initial time of diagnosis, and they're treated aggressively at the time with 4 cycles of BEP or 4 cycles of VIP chemotherapy. And then they go for surgery to remove any residual disease. And the hope is they're cured at that point because historically, if there was a relapse after chemotherapy and surgery, it was almost impossible to cure them. Indiana University published their results using high-dose chemotherapy in this population, and they reported that 30% of men who were treated with high-dose chemotherapy had no evidence of cancer after 2 years, and 35% were still alive. Obviously, we need longer follow-up, but most of the relapses you're going to see are going to be in the first 2 years. So while again, there is significant room for improvement here, this indicates that high-dose chemotherapy is a good option, and that has been a question. So this is reassuring in that regard. But it is a good option for men with relapsed mediastinal non-seminomas of the germ cell tumors. So there's hope there where in the past, this has felt a little bit helpless. The thing I wanted to also highlight was that there are 3 things I think are going to be interesting to keep an eye on over the next year. One is the use of surgery for early-stage seminomas. There are a number of papers out about that. I still think this is an investigational approach, and so I didn't want to go into great detail about it, but it is looking like that RPLND, or retroperitoneal lymph node dissection, will likely or may be an option for stage I and stage II seminoma in the future. We are getting more evidence for that. It's not quite as promising as we had hoped until there's more data that's needed, but it's looking like that will become an option. So for men with early-stage seminoma, at least raising the question whether surgery is an alternative to chemotherapy or radiation, is an important discussion to have with your oncologist. Secondly, MRI rather than CT scans for surveillance. So to keep an eye on men who have been treated or men who are just stage I and are being followed and typically come in routinely for CT scans, which expose people to ionizing radiation, which theoretically has a risk of causing cancer, there's more and more data that MRI is just as good as CT, and MRI does not use ionizing radiation. So there's probably going to be an expanding role for MRI as an alternative to CT scans. And lastly, the use of microRNA rather than just depending on serum tumor markers. So right now, we use the blood tests alpha-fetoprotein, beta hCG, extensively to monitor for relapse, and there's more and more evidence for using what we call microRNAs instead. It may be more accurate in multiple different settings. So it'll be interesting to see how that evolves and that's what I wanted to cover today. Thank you very much. Greg Guthrie: Thank you, Dr. Gilligan. And now we have Dr. Grivas, who's going to discuss some research in bladder cancer. Dr. Grivas: Thank you so much, Greg, and thanks Cancer.Net for the great opportunity to discuss this for our patients. We're very excited about the data from the ASCO Annual Meeting, and I would encourage the audience to review as possible other presentations as well. I'm going to cover 3 highlights. I'm going to start with the QUILT-3.032 study. This trial reported the final results of a clinical trial that took place in different centers and involved patients with what we used to call “superficial bladder cancer.” And the modern term is “non-muscle-invasive bladder cancer.” Bladder cancer that does not involve the muscle layers, not that deep in the bladder wall. Non-muscle-invasive bladder cancer is usually treated by our colleagues in urology with installation inside the bladder with an older form of immunotherapy which is BCG. And that's the most common way we treat this disease. And proportion of patients may have tumors that may not respond to BCG that may come back or persist despite the installation of the BCG in the bladder. And these patients usually have a standard of care of getting what we call radical cystectomy, meaning, removal of the bladder and the lymph nodes around the bladder, radical cystectomy and lymph node dissection. However, many patients may not have, I would say, the opportunity to get the surgery because the body may not be that strong to undergo that significant procedure. Very few patients may have that challenge because of other medical conditions or what we call poor performance status. Or some patients for quality-of-life reasons may try to keep their bladder as long as possible. And for some of those patients, that might be an option. And we have been looking for those options in the last few years. Intravesical, inside the bladder, installations of chemotherapy have been used with some positive results in some other studies. So that's an opportunity. We call this intravesical, inside the bladder, installations of chemotherapy, and the other option is an FDA-approved agent given intravenously inside the vein called pembrolizumab, which is in the form of immunotherapy. Of course, research continues. And this study I'm showing here from Dr. Chamie and colleagues, looked at this combination of BCG plus this molecule called N-803. This is another form of immunotherapy, and this was tested in patients who have this BCG-unresponsive, as we called it, non-muscle-invasive bladder cancer. The results were very promising. I would say impressive that it was a high response rate if we focus our attention on patients who had the superficial form carcinoma in situ, about 70% had no evidence of cancer upon further evaluation of the bladder. And in many of those patients that this response lasted for more than 2 years. 96% of patients avoided to have worsening of the bladder cancer in 2 years for those who had a response, and about 9 out of 10 avoided cystectomy again from those patients who had received the response. So it was 70% of all the population. And as you see, all patients, 100% were alive without dying from bladder cancer after 2 years, which again is a very promising finding. This combination, to conclude, this inside the bladder installations of BCG plus the N-803, looks very promising. For those patients with BCG-unresponsive non-muscle-invasive bladder cancer, that might be an option down the road, we have to see. Now I'm going to shift my attention to patients with metastatic or spread urothelial cancer. I want to point out that I'm a co-author in this abstract and I participated in that survey I will show you the results from. This is a population of patients who have spread cancer from the urinary tract, either the bladder was the most common origin or other parts of the urinary tract, for example, what we call kidney, pelvis and ureter, or rarely the urethra. The urothelial cancer that starts from those areas, again more commonly bladder, if it spreads, if it goes outside the urinary tract system, usually those patients get chemotherapy, what we call with an agent called cisplatin if they can tolerate that chemotherapy drug or carboplatin if they cannot tolerate the cisplatin drug. And usually either of these, cisplatin or carboplatin, is combined with a drug called gemcitabine. That's the most common chemotherapy used as initial therapy for patients with spread metastatic urothelial cancer. In this abstract, Dr. Gupta and colleagues tried to survey 60 medical oncologists, including myself, who treat urothelial cancer that considered experts in this disease type, to see if there are any features that could deter us from using chemotherapy in those patients. In other words, are there any features that may make us think that chemotherapy may be too risky for our patients and we should not do it? We should give immunotherapy instead. This is probably a small proportion of our patients, maybe 10 to 20% in our practice, may not be able tolerate that chemotherapy. And which are those features? Poor performance status, meaning the body is very tired and the patient is not moving too much, is confined in the chair or the bed most of the day, and rely on others on daily activities. This is what defines the performance status of ECOG 3. Peripheral neuropathy, meaning that there is numbness or tingling or weakness in the hands or the feet that impact the quality of life. And patients may have trouble buttoning buttons or tying laces, so impacting the quality of life. That's grade 2 neuropathy. Symptomatic severe heart failure, there is a grading system, like New York Heart Association Class III or IV that is significant, notable heart failure symptoms. And also, patients with kidney failure with what we call creatinine clearance below 30 cc per minute. That's a marker how we measure kidney function and the creatinine clearance more than 60 is usually close to normal. As the creatinine clearance drops and goes below 30, chemotherapy with these platinum agents may become a challenge by itself or if it's combined with the ECOG performance status of 2, which means more patients are not moving most of the day. So those features again have to do with the functionality of the day-to-day life. The presence of significant neuropathy, heart failure, and poor kidney function may potentially make the oncologist recommend immunotherapy versus the standard of care, which is chemotherapy, in those patients. And I would say if someone gets chemotherapy, which is the majority of patients, usually they may get immunotherapy later. So pretty much I would say discuss with the medical oncologist what is the right treatment for you. Most patients get chemotherapy up front, followed by immunotherapy. Some others may need to get immunotherapy, and those criteria help us make that patient selection for the right treatment at the right time. So I just alluded to you that most patients with spread or metastatic urothelial cancer, most of them receive chemotherapy. We discussed some criteria in the previous studies that we may use immunotherapy upfront instead of chemo, but for the vast majority of patients, chemotherapy is used upfront and that was based on the results of phase 3 clinical trial called JAVELIN Bladder 100. This was presented at the ASCO Annual Meeting in 2020 about 2 years ago, and it was published in a big journal. And that study showed that if you give chemotherapy upfront, those patients who can tolerate the chemotherapy, of course, who do not have the previously listed criteria, those patients benefit and live longer, so longer overall survival, meaning they live longer, and they have longer progression-free survival, meaning they live longer without worsening of the cancer if they get immunotherapy with, immunotherapy drug is given through the vein, called avelumab. If that is given after the end of chemotherapy for patients who have a response or stable disease, meaning no progression on chemotherapy. So if you get a complete response, meaning that the CAT scans look normal after chemotherapy as at least we can tell visually. Partial response, meaning that the CAT scans look better, but still we can see some cancer spots. Stable disease, meaning that the scans look stable compared to the beginning before we start chemotherapy. If someone has worsening of the cancer in chemotherapy, then the concept of maintenance therapy doesn't apply. So it's only for patients with complete response, partial response, or stable disease, SD. And the poster we had, and I can tell you - I was a co-author in the abstract and co-investigator in the trial, as a disclosure - was sort of the benefit of the patient with avelumab as maintenance therapy after chemotherapy was notable in patients with complete response, partial response, and stable disease. So in any of these 3 categories, avelumab immunotherapy should be offered as level 1 evidence and benefit patients in terms of overall survival and progression-free survival as long as there's no progression to the upfront initial chemotherapy of the patient with metastatic urothelial cancer received. Many other abstracts on these cancers were presented, and I would encourage you to look at them. Thank you so much for the opportunity today. Greg Guthrie: And thank you, Dr. Grivas. Next, we have Dr. Zhang who will discuss some research in kidney cancer. Dr. Zhang: Hi everyone, glad to be here today. I'll be discussing 2 highlights from ASCO 2022 in kidney cancer. The first one we wanted to highlight was a trial called EVEREST: everolimus for renal cancer ensuing surgical therapy, a phase 3 study. And in context, this study is a trial of evaluating everolimus, an mTOR inhibitor, in the post-surgical context. And we do have in the landscape 2 approved therapies, sunitinib and pembrolizumab. And as we have seen, some effective therapies in the refractory setting, many of these therapies are being tested in this postoperative space. So this particular study of EVEREST looked at patients with renal cell carcinoma who underwent resection for their primary nephrectomy and looking to evaluate postsurgical treatment. So everolimus has been approved as a treatment on its own in the refractory setting as well as in combination with lenvatinib. And so this question of whether everolimus alone could delay or prevent disease recurrence in the postoperative setting was tested in this EVEREST trial. The study ultimately enrolled more than 1,500 patients and assigned them to receiving either everolimus or placebo in the postoperative setting. Of these patients, 83% had clear cell kidney cancer and the remaining had non-clear cell kidney cancer. And the follow-up was quite long, over 5 years, and actually over 6 years, and the researchers looked at time until disease recurrence. And risk of recurrence was actually decreased by 15% in patients who were treated with everolimus compared to placebo. But the prespecified cut-off for a statistical significance was not quite reached, and the researchers took a specific look at a group of very high-risk patients defined by larger tumors, invasion of the perinephric fat in renal veins or invasion of nearby organs or known positive disease. And those patients with very high-risk disease had more benefit from everolimus compared to placebo. Of note, 37% of patients who were treated with everolimus had to stop treatment due to their side effects, and the most common severe side effects included mouth ulcers, high triglyceride levels, and high blood sugars. So ultimately this particular study did not show sufficient benefit of everolimus given the toxicity and lack of statistical significance. And so this is a balance between potential benefit in delaying recurrence versus treatment toxicities that we must have in this adjuvant setting. So what does this particular study mean for patients? Well, it was certainly a large phase 3 trial performed in the cooperative group setting and through the generosity of 1,500 patients and the principal investigators on the study, we learned this answer for a very important question of whether everolimus makes a difference in this postoperative setting. I think we're not using this in clinical context currently, but in this postoperative setting, we are always balancing this risk of toxicity with the potential for benefit and discussing the potential treatment options. I do not think this particular trial changes the standard of care in this adjuvant setting. And then I think finally for today's prepared talks, this abstract on depth of response and association with clinical outcomes with CheckMate 9ER patients treated with cabozantinib and nivolumab. So this was a post-trial analysis of patients who had kidney cancer with disease spread and treated with cabozantinib and nivolumab compared with sunitinib in the CheckMate 9ER study. And the context, this was the phase 3 trial in which the benefit of cabozantinib and nivolumab was established in the first-line setting and gained the registration and approval of this combination in the first-line treatment of metastatic kidney cancer. This particular analysis, presented at ASCO this year, was a post-trial prespecified analysis evaluating this depth of partial responses and associating those with clinical outcomes of time until disease progression as well as time until death. These depth of responses were defined as 80 to 100% for PR-1, 60 to 80% for PR-2, and then 30 to 60% as PR-3. And as we saw in this analysis, the deeper the responses on cabozantinib and nivolumab, the more correspondence with higher 12-month rates of disease-free progression compared with those same depths of responses from sunitinib. And there were similar 12-month overall survival rates for patients with similar depth of responses for either the cabozantinib and nivolumab combination compared with sunitinib. So I do think the degree of partial response in these settings is productive of time until progression and establishes further the efficacy and benefit of cabozantinib and nivolumab compared with sunitinib. And what does this trial mean for our patients? I think that early on, as we're looking for responses and radiographic changes for our patients on cabozantinib, nivolumab in the first-line setting, these deeper responses are associated with longer time until disease progression, and we can counsel patients, to discuss whether cabozantinib and nivolumab is working for them. This could be an early indicator for how patients will do overall on this combination. So with that I'd love to wrap up and turn it back over to you, Greg. Greg Guthrie: Thanks so much Dr. Zhang. And now it's time to move on into our Q&A session. This is for you, Dr. Agarwal. So the question is utility of triple therapy, ADT plus docetaxel plus ASI and metastatic hormone-sensitive prostate cancer given ENZAMET was inconsistent with PEACE-1 and ARASENS. Would you give ASI concurrent or sequential after chemotherapy for tolerability? I'm assuming ASI here is androgen suppression, correct? Dr. Agarwal: Yes. Great question. There are 2 questions here. Number 1, if I would use triplet therapy given the negative subgroup analysis of the ENZAMET trial, and number 2, what is the role of triplet therapy in general? The answer to the first question is ENZAMET trial, subgroup analysis is very different from preplanned, prespecified, well-powered analysis from PEACE-1 and the ARASENS trial. So yes, we saw discrepant results, but my impression from ENZAMET trial is enzalutamide is an effective option for all patients regardless of the receipt of docetaxel chemotherapy because that was a subgroup analysis. So I don't think it really affects negatively the results of the ARASENS and the PEACE-1 trial. But a bigger question here is triplet therapy versus doublet therapy? Is triplet therapy for all or doublet therapy for all? Answer is no. Triplet therapy trials only showed that adding a novel hormonal therapy or deeper androgen blockade to the backbone of ADT plus docetaxel improves survival. These trials did not answer the question, if adding docetaxel chemotherapy to ADT plus, for example, enzalutamide or darolutamide or apalutamide, will improve survival. We do not have that question answered by any of the trials and unlikely any other trial will answer that question. So my take ADT plus docetaxel is replaced by ADT plus docetaxel plus these deeper androgen blocker therapy. So wherever I was going to use docetaxel chemotherapy, so those are the patients with visceral metastases or in my practice, when I do comprehensive genomic profiling, I see those molecular aberrations which predict lack of response to deeper androgen blockade such as baseline AR variants. Or if I see 2 out of 3 mutations of p53, RB loss, p10 loss, if I see 2 out of these 3, I tend to think about docetaxel chemotherapy. So in those patients where I'm using ADT plus docetaxel, I would add another androgen receptor blocker such as abiraterone and darolutamide. But when I'm using enzalutamide or apalutamide which I use for majority of those patients, my patients with metastatic hormone-sensitive prostate cancer, I do not think about triplet therapy. Greg Guthrie: Thanks, Dr. Agarwal. We actually have a follow-up question, and this is, what is the role of oncology in low-stage early prostate cancer? Can neoadjuvant chemotherapy reduce the number of people who end up with metastatic prostate cancer? Dr. Agarwal: This answer is very simple. There is no role of neoadjuvant chemotherapy in high-risk localized prostate cancer or any localized prostate cancer setting. Greg Guthrie: Great. Thank you. Next question. I believe that this is for everybody. How long will it be until the information from the trials discussed will be used in the community clinics? What can patients do to bring this information to their less experienced doctors? Dr. Grivas: So, Greg, just to clarify the question, is it about the translation of the results of the clinic from ASCO to clinical practice, generically speaking, or any particular tumor type or any particular data results? Greg Guthrie: The way I read this question, it's more just kind of a broader scope question about just like, how long does the results of clinical trials make it to community practice, and what role can patients have in perhaps fostering this transmission of information? Dr. Grivas: Of course, I can start briefly, and then my colleagues can add. I would say the world we live in right now, the information travels very quickly. It's much faster compared to the past. And I think there is much more alignment, in my opinion, in terms of information access between academic oncologists and community oncologists. If, for example, a trial result comes at ASCO being presented, and then there's a follow-up approval authority from a regulatory agency, this agent may be accessible to both community and academic practices. Of course, there are always opportunities for education, and Dr. Agarwal is the director of the ASCO Daily News, and he knows that well to disseminate the information well, broadly, in an equitable manner across academic oncologist providers and community providers. And I think CME, continued medical education practices, can help in that regard. And obviously, the other aspect of that is the ongoing clinical trials and how we can do a better job disseminating the opportunity for equitable participation in clinical trials across racial groups, ethnicity groups, minority groups, to give them the chance to participate in ongoing clinical trials that may change the practice down the road, which are just early thoughts. But other colleagues can comment. Dr. Zhang: Yeah, if I could chime in. I think these continuing medical education programs, particularly in the context after large symposia like the ASCO Annual Meeting we just had, are particularly important. And the Best of ASCO series, as well as ASCO Direct Highlight series - I believe Dr. Grivas and I are hosting 2 of these - are very helpful, I think, to bring the latest findings from the ASCO Annual Meeting to our community colleagues. And they really are our colleagues. We work together with our oncologists within the community to take care of our patients, oftentimes for standard of care treatments. Patients can access them more in their backyards. And I think from a patient standpoint on the second part of the question, they're able to hear these from patient-friendly platforms and to bring that to the attention of their oncologist, wherever that may be. It all helps in the grand context of clinical care. So I hope that these trial results and the latest findings from ASCO can get inseminated very quickly.   Dr. Grivas: And to also add very briefly, the role of patient advocacy groups, and in the bladder cancer work, there are many, for example, the Bladder Cancer Advocacy Network, World Bladder Cancer Coalition, and many others can help also in that regard and teaming up with all of us to disseminate information and also clinical trial access. Greg Guthrie: Great. Thank you, everyone. We have a question for Dr. Grivas. After the survey results in the study you described, is there any plan to make a guideline or tool to make sure we standardize the definition of cisplatin/platinum ineligibility? Dr. Grivas: Great question. Just 1 more thing on my prior answer, kudos to Cancer.Net for serving that mission, Greg and Claire in that-- or the previous question to have a complete answer. Answering this new question here, which is very important. I think the next step is to try to publish the results of the survey. The survey like the previous one done by Dr. Galski about 10 years ago-- it's a survey on expert oncologists, and it's a consensus-based definition. It's criteria that we came up with together. And I think the next step here is to publish this in a peer-review process. And our hope is by publishing these results, we can have a more formal definition to help guide our practices in academia, but also in the community oncology practices and make sure that we have a standardized way that we approach this therapy selection and of course, to help design clinical trials that for this particular patient population in order to improve outcomes in this setting. So hopefully publication will come soon. Greg Guthrie: Thanks, Dr. Grivas. I'll just drop a really quick pitch there. Here at Cancer.Net, we do have a very broad array of information on clinical trials. And patients can come visit us at Cancer.Net and learn about clinical trials, what they mean, and how they help advance cancer research. We now have a question for Dr. Zhang. Based on the results of EVEREST and other trials approved systemic therapies in the adjuvant setting like sunitinib and pembrolizumab, are there ongoing other trials in this setting and is risk stratification used? Dr. Zhang: The short answer is yes. There are ongoing adjuvant trials that build on pembrolizumab in the adjuvant setting. There's one that is looking at the addition of belzutifan with pembrolizumab in the adjuvant setting. So that trial is a global trial which is about to get started, if not enrolling already. And in the context of adding on in the adjuvant setting, I do think we really need to discuss with our patients how much of a benefit the treatment will have versus the real toxicity in the postoperative setting, many patients will not have symptoms from their cancer, so they may have some pain or healing side effects from surgery, but they won't have symptoms from cancer. So any toxicities from medications can be further amplified, so are we truly giving a lot of benefit in that context or not. So that's an individualized decision, and I do think conversations must be had to make that decision together. Greg Guthrie: Thanks, Dr. Zhang. I want to ask a question myself of Dr. Gilligan. You had mentioned that microRNA is an emerging field of study, and I've heard about this in other types of cancer as well. I wonder if you could discuss that a little bit more. Dr. Gilligan: Yeah, microRNA, the promise that holds is being a more accurate detector, specifically of testicular cancer. So the problem we have with alpha fetoprotein and beta HCG is half of the testicular cancers may not make 1 or both of those markers. So people can relapse without the markers going up, even though markers are most commonly what we see, there are a couple of different scenarios. Someone has stage I testicular cancer, which means their testicles removed and all their scans show no evidence of cancer. We know that 25% or so of non-seminomas and 20% or so of seminomas will relapse, even though we can't see what the cancer is, and the markers are negative in that situation. MicroRNA may be able to detect those people who still have cancer much, much earlier. So we know that they're, in fact, not stage I and that they need active treatment right away. So that's one place. Another place that we're seeing evidence is that men who've had metastatic testicular cancer. They go through chemotherapy, and they have residual masses. And we're wondering if there's cancer in those masses or is it all dead scar tissue or is it teratoma? MicroRNAs may be able to allow us to determine who needs additional treatment, who needs surgery without having it. Right now, we typically go in and operate just to figure that out. So there are a number of situations in which we could more accurately stage patients and figure out who's cured and who's not cured much earlier in the course of disease. And for a patient, this would be fantastic, because right now, if you've got stage I disease with non-seminomas and you go on surveillance and somebody says you have a 25% risk the cancer is going to come back, that's a 1 in 4 chance that at some point in the next 2 years, most likely, or longer, you're going to have to suddenly drop everything and go through months of chemotherapy. If we knew on day 1, it looks like you're cured, but in fact, there's cancer hiding there somewhere, and we need to treat you now, that would be helpful to know so they can get it over with. And the other men, we could say we're really extremely confident that there's not a 25% risk, it's a 5% risk or something much lower. So there are a number of ways, if this really gets proven and there's emerging data that's promising, I think we could reassure men, treat them more appropriately, spare them unnecessary treatment, and give them more peace of mind. Greg Guthrie: Great. Thanks, Dr. Gilligan. I think we have a question from Dr. Grivas now. Dr. Grivas: Thank you, Greg. This is a great panel. I like to learn from my colleagues here. One question for Dr. Zhang, you have done so much work in the field, leading the field there, Dr. Zhang. Any comments about the ideal end points in the adjuvant setting in kidney cancer, urothelial cancer, disease-free survival or overall survival? Would you comment about how we design trials, and what will be an acceptable benchmark? And what is meaningful for patients, too, in the adjuvant treatment after radical surgery for kidney cancer and urothelial cancer? Dr. Zhang: Oh, that's a great question, Petros. Thank you so much for asking. We have discussed this many times together because you and bladder cancer and myself and kidney cancer, we're thinking a lot along the same lines right as new immunotherapies get approved in the postoperative setting, so disease-free survival as an endpoint and recurrence-free survival as an endpoint is a valid endpoint. It's a direct result of the randomized treatment on the trial, so I do think that is the valid endpoint, and it's an endpoint that the FDA has approved the sunitinib and pembrolizumab indications in kidney cancer, nivolumab and bladder cancer. So I think it's certainly a valid endpoint to delay disease recurrence. How much of that is meaningful degree of improvement for an individual patient? Their own measure of recurrence is either yes or no. It's much more binary than population effects. So how much does that translate into benefits for the patient? I think that warrants deeper individualized discussion. But these disease-free survival endpoints in all of these studies is a valid endpoint to see whether the treatment is worthy in delaying disease recurrence in each of these disease types. Greg Guthrie: Thanks, Dr. Zhang. We have one last question here, and I believe this is a follow-up for Dr. Gilligan. And what is the time frame for the rollout of microRNA 371 to the community? Dr. Gilligan: I don't know the answer to that. I'm not sure that we have enough data right now that it's going to get approved. I think we're headed in the right direction, but it's very hard to know what the timing of that is. There are trials going on, so I don't know at the moment of exactly what the scenarios are in which people are going to be, which patient populations are going to be eligible, but there are trials going on. I think I'm hoping within the next 2 years or so, but I really don't know what the time frame is, unfortunately. Dr. Grivas: And if I may add a more generic comment to Dr. Gilligan's wonderful answer is that when we have what we call biomarkers that are like metrics that can give us information about how the patient does over time, it's important to tease out what we call prognostic, meaning how can this biomarker give us a sense of the chance of recurrence, as Dr. Gilligan said, or death from the cancer. But also, the bigger question is, is it going to give us information to predict benefit from an individual therapy? And that's a bigger question in oncology that is a harder one. This predictive question and try to identify biomarkers and validate them to make sure they have, they're clinically useful. They can help us make treatment decisions in the clinic. And I'm very excited about what Dr. Gilligan discussed about the promise in the future. But more trials are needed for many biomarkers. Dr. Gilligan: I think when we do this update next year, we'll have significantly more data then, I'm hopeful. Greg Guthrie: Thank you to you all. Thank you, Dr. Agarwal. Thank you, Dr. Grivas. Thank you, Dr. Gilligan. Thank you, Dr. Zhang, for sharing this great research with us, as well as your expertise. It's been a real pleasure this afternoon. And to all of our viewers, thank you for joining us. You can find more coverage of the research from ASCO Annual Meeting and other scientific meetings at the Cancer.Net blog, which is at www.cancer.net/blog. And if you're interested in more Cancer.Net content, please sign up for a monthly Inside Cancer.Net newsletter or follow us on social media. We're on Facebook, Twitter, and YouTube where our handle is always @CancerDotNet, with dot spelled out. Thank you all, and be well. Thanks. ASCO: Thank you, Dr. Agarwal, Dr. Gilligan, Dr. Grivas, and Dr. Zhang. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Rene Pareja to discuss conservative management of cervical cancer. Dr. Pareja is a gynecologist-oncologist at Astorga Oncology Clinic in Medellín and the National Cancer Institute in Bogotá, Colombia. He is a reviewer for more than 20 specialty journals, an Associate Editor for IJGC, a member of the Editorial Board of Gynecology Oncology, and a member of the board of directors of the International Gynecological Cancer Society (IGCS). Additionally, he is a member of FIGO committee on Women's Cancer. Dr. Pareja is the author of nine book chapters and more than 70 publications in peer-reviewed journals, and at IGCS 2021 he received an award for Community Advancement in Resource-Limited Settings. Highlights: 1. Fertility preserving options have to be offered to all women wishing to preserve their fertility potential, that fulfil the ECOG status, histological, and imaging criteria. 2. It is recommended to have an evaluation by human reproduction specialized teams in order to rule out any potential impairment before the surgery. 3. The relapse rate for vaginal radical trachelectomy, abdominal radical trachelectomy and simple trachelectomy/conization are around 4-5%. 4. The highest live birth rates are seen in patients undergoing conization + lymph node assessment (over 88%). 5. Vaginal radical trachelectomy and minimally invasive radical trachelectomy, with preservation of ascendent branch of uterine artery, are contraindicated in women with tumors > 2 cm, due to the high rate of relapse (over 20%).

In der Mittagsfolge sprechen wir heute mit Johannes Weber, Managing Director und Founder von Ananda Impact Ventures, über das Final Closing desseines vierten Core Impact Fund mit einer Gesamtsumme von 108 Millionen Euro. Der europäische Impact Investment Fund namens Ananda Impact Ventures wurde im Jahr 2009 von Johannes Weber und Florian Erber in München gegründet und hat mittlerweile noch einen weiteren Sitz in London. Der VC investiert in Impact Startups, die Lösungen für gesellschaftliche Herausforderungen finden. Dabei fokussiert sich der VC für Social Entrepreneurs hauptsächlich auf den DACH-Raum und UK. Das 13-köpfige Team hat ein Portfolio von 32 europäischen Startups in den Bereichen Digital Health, Education, Ageing, Future of Work und nachhaltiger Konsum aufgebaut. Darunter zählen u.a. NatureMetrics, Resourcify, OroraTech, EcoG, DrDoctor, Doktor24, Voiio, Mika, Caspar, Talea, Raremark, MobileJob, Hometouch, Careship, Company Bike, Vitabook und Open Bionics. In einem Final Closing hat Ananda Impact Ventures mit seinem vierten Core Impact Fund 108 Millionen Euro gesichert und damit den Zielwert von 75 Millionen Euro mit 44% signifikant überschritten. Bereits beim First Closing erreichte der Fonds 65 Millionen Euro. Zu den Investoren des Impact Investment Fund zählen der Europäische Investitionsfonds (EIF), KfW Capital, Investcorp-Tages, Candriam und mehrere Family Offices.

Guest host Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute and the ASCO Daily News editor-in-chief, discusses key therapeutic advances in mRCC and mUC, as well as new research that proposes periodic scans to monitor patients with mCSPC for disease progression, with Dr. Jeanny-Aragon-Ching of the Inova Schar Cancer Institute.  Transcript:  Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.  My guest today is Dr. Jeanny Aragon-Ching, who is a medical oncologist and the Clinical Program Director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia.  Today, we will be discussing key posters in genitourinary (GU) oncology that will be featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcast.  Jeanny, it is great to have you on the podcast today.  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. It's a pleasure for me to be here as well.  Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4510. This is a trial that represents a growing interest among researchers worldwide in the microbiome and how it is impacted by antibiotics and how it modulates immune checkpoint inhibitor response. Can you tell us about this study?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj, I would be happy to. So, the title of the abstract is, “Characterization of the Microbial Resistome in a Prospective Trial of CBM 588 in Metastatic Renal Cell Carcinoma Offers Mechanism for Interplay Between Antibiotic Use and Immune Checkpoint Inhibitor Activity.”  So, this is an interesting abstract that originated likely from the observation that getting antibiotics while on checkpoint inhibitors typically results in worse outcomes, perhaps because antibiotics can clear the normal gut flora and thereby increase these pathogenic antibiotic-resistant bacteria.  Now, on the other hand, there were some retrospective studies using a live microbial product called CBM 588, which seems to improve outcomes in patients on checkpoint inhibitors and getting antibiotics.  So, the idea, therefore, is that shifting the genes encoding antimicrobial resistance could result in a better checkpoint inhibitor response. So, this Abstract 4510 is a small study conducted by Dr. Nazli Dizman and Dr. Sumanta (Monty) Kumar Pal, and colleagues, and enrolled 29 metastatic clear cell RCC patients with intermediate or poorest disease. And they were stratified into receiving either nivolumab or ipilimumab compared to nivo/IPI with CBM 588.  Now stool samples were collected at baseline in week 12. And they did this whole metagenome sequencing to analyze a stool microbiome composition, and they also looked at the antibiotic resistance genes for the most common classes of antibiotics.  The results showed an astounding improvement in objective responses. So, 58%, for instance, in nivo/IPI and the CBM 588 arm compared to only 20% in the nivo/IPI arm. And it seems like also the antibiotics resistance genes were also decreased in those getting the CBM 588 alongside nivo/IPI. Therefore, responses were improved by shifting the gut microbiome alone. So, these findings were published actually recently by these authors in Nature Medicine. So, in case anyone wants to take a deep dive, it would be a good interesting read for this dataset.  Dr. Neeraj Agarwal: Very interesting, indeed. Jeanny, what is the main message here for our colleagues?  Dr. Jeanny Aragon-Ching: I think, Neeraj, the key takeaway message is that this is a very provocative proof of concept trial that suggests shifting the gut microbiome has the potential to improve responses to checkpoint inhibitors and outcomes. So, this is a very up-and-coming trial and is seen also across the board in other cancers.  Dr. Neeraj Agarwal: Thanks, Jeanny. Moving on to urothelial cancer, there is a poster that I think is a must-see for our colleagues. This is Abstract 4577 titled, “Defining Platinum Ineligible Patients with Metastatic Urothelial Carcinoma.”  Dr. Jeanny Aragon-Ching: So, Neeraj, what can you tell us about this abstract?  Dr. Neeraj Agarwal: So, over the past few years, there has been a tremendous evolution in the treatment landscape for patients with metastatic urothelial carcinoma. For over 40 years the standard of care for these patients has been cisplatin-based chemotherapy.  However, approximately 50% of patients are cisplatin-ineligible, due to underlying comorbidities, and are offered carboplatin as an alternative. So, although the checkpoint inhibitors pembrolizumab and atezolizumab were approved as first-line therapy for these patients in 2017, the U.S. Food and Drug Administration (FDA) has now restricted the use of first-line pembrolizumab to platinum ineligible patients with metastatic urothelial carcinoma.  The challenge we face as oncologists since the FDA restriction is the absence of a formal definition of platinum ineligibility and the inclusion of this definition in the guidelines. So, in Abstract 4577, Drs. Shilpa Gupta and Jonathan Rosenberg, along with the team present an updated consensus definition for platinum ineligibility based on an online survey of 60 genitourinary oncologists in the United States.  Based on the results from this survey, any patient with metastatic urothelial carcinoma, meeting 1 of the following 5 clinical and or laboratory parameters should be considered platinum ineligible, and these are 1 of the following: an ECOG performance status of 3 or more, creatinine clearance of fewer than 30 mils per minute, or peripheral neuropathy of grade 2 or more, or heart failure class of 3 or more—so, this is NYHA heart failure class of 3 or more—and lastly, the combination of performance status of 2 or more, plus a creatinine clearance of less than 30 mils per minute.  Dr. Jeanny Aragon-Ching: Well, this is a timely update, Neeraj. So, what do you think is a key takeaway from this abstract?  Dr. Neeraj Agarwal: These criteria based on simple and easily available clinical and or laboratory parameters will now allow us to readily define platinum ineligibility in our patients with metastatic urothelial carcinoma, which is a need in busy clinics, both in academic and community settings.  So, I think once published and obviously once endorsed by guidelines, we really would like to be able to use this criterion to quickly define platinum ineligibility in our clinics.  Dr. Jeanny Aragon-Ching: Agree. Yeah.  Dr. Neeraj Agarwal: So, Jeanny, let me switch the gears. PSMA testing is a hot topic this year. And there is an abstract that could potentially have an impact on future guidelines, and how we will practice further down the road.  So, I'm referring to the Abstract 5088 titled, “Predictive Value of Extra Prostatic Disease Detection by Preoperative PSMAPET for Biochemical Recurrence-free Survival in Patients with Otherwise Localized Prostate Cancer and Who are Treated with Radical Prostatectomy.”  So, this is a follow-up analysis of a multicenter prospective phase 3 imaging trial. So, could you please tell us more about this abstract where they are using PSMA PET scan in the preoperative localized prostate cancer setting?  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, you may recall that the multicenter prospective phase 3 imaging trial that garnered gallium PSMA approval by the FDA was actually based on this study that looked at the intermediate and high-risk patients with prostate cancer undergoing radical prostatectomy and lymph node dissection, and they underwent prior gallium PSMA PET scanning for pelvic nodal metastases prior to surgery.  So, this was actually previously reported by Dr. Calais and group. Now they are reporting on Abstract 5088 as a post hoc analysis of the same population and group of patients looking for extraprostatic disease. And the final pathology was also correlated to look at nodal disease in these patients in order to predict biochemical recurrence, so they follow these patients for biochemical recurrence occurrence.  So, of the 36% of patients who did undergo radical prostatectomy after they underwent PSMA PET scan, about 41% of them recurred with biochemical recurrence, and 40% of them underwent some kind of salvage therapy or some treatment.  What was very interesting was when they looked at the biochemical recurrence-free survival. It was better in those who were PSMA negative, and that recurrence-free survival was easily about 33 months, compared to only about 7.3 months in those who were PSMA-positive scans.  Furthermore, the ones who had the longest and the highest biochemical recurrence-free survival, intuitively, were those who were node-negative and PSMA PET-negative, so probably not surprisingly. And that rate was about 46 months—close to 4 years. Whereas those who are node-positive on final pathology and their PSMA PET was also positive, they only had about 3 months of biochemical recurrence-free survival.  Dr. Neeraj Agarwal: Very interesting. So, it looks like the PSMA PET scan is predicting biochemical recurrence-free survival in localized prostate cancer settings. So, Jeanny, what is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: I think, Neeraj, the bottom line is that patients with extraprostatic disease that is detected by their preoperative PSMA PET scan does predict strongly a high risk of biochemical relapse, and this can really be an additional tool that clinicians can use to help inform and guide future therapy.  Dr. Neeraj Agarwal: Thanks, Jeanny. The research on preoperative PSMA testing and its implications on future treatment strategies in the setting is going to be really interesting to watch in the very near future.  Dr. Jeanny Aragon-Ching: Yes, absolutely. I really think we should also discuss Abstract 5072, along those lines, the importance really of radiographic monitoring for disease progression in patients with metastatic hormone-sensitive prostate cancer.  Dr. Neeraj Agarwal: Yes, thanks for reminding and this is Abstract 5072. This is a post hoc analysis of the ARCHES trial, titled, “Radiographic Progression in the Absence of PSA Progression in Patients with Metastatic Hormone-sensitive Prostate Cancer.”  During the last several years, we have seen many of these agents typically given for gastric resistant prostate cancer moving upfront to the castration-sensitive prostate cancer setting. This is especially true for androgen receptor access targeting agents such as abiraterone, enzalutamide, and apalutamide, all being now approved for patients with metastatic castration-sensitive prostate cancer.  What is noteworthy from all these trials, and is reported in Abstract 5072, is the use of imaging studies to evaluate disease progression. So, in Abstract 5072, Dr. Andrew Armstrong and Dr. Arun Azad performed a post hoc analysis of the ARCHES trial to investigate the concordance between radiographic progression and the PSA Progression as defined by PCWG2 criteria, or between radiographic progression and any rise in the PSA above nadir, in patients who were being treated with this novel hormonal therapies, in this case, enzalutamide for metastatic castration sensitive prostate cancer.  And as a quick reminder, ARCHES was a phase 3 trial that showed a significant reduction and radiographic progression-free survival and improved overall survival for patients with metastatic castration sensitive prostate cancer treated with enzalutamide plus androgen deprivation therapy (ADT) versus those treated with placebo plus androgen deprivation therapy.  So, very interestingly, the findings from this study indicate that 67% of patients on the enzalutamide plus ADT arm did not have [Prostate Cancer Clinical Trials Working Group 2 criteria] PCWG2-defined prostate-specific antigen (PSA) progression at the time of radiographic progression. And discordance was present in the ADT-only arm as well, where they found 42% of patients on the ADT-only arm had radiographic progression but did not have PCWG2-defined PSA progression.  Interestingly, this discordance of radiographic disease progression was also seen with any rise in the PSA above nadir. And I personally found this information to be very clinically relevant when we are seeing the majority of patients actually experiencing radiographic disease progression, not experiencing PSA progression at the same time.  Dr. Jeanny Aragon-Ching: Yeah, absolutely. I agree with that, Neeraj. So, very interesting data. So, what do you think is the key takeaway message for the clinicians listening to us?  Dr. Neeraj Agarwal: I'll make the message very simple. I think the message is that patients with metastatic castration-sensitive prostate cancer need to be monitored for disease progression with periodic scans, and PSA monitoring alone is not sufficient in the majority of these patients.  Again, we cannot undervalue the role of periodic imaging studies in these patients so that we can timely diagnose them to have disease progression.  Dr. Jeanny Aragon-Ching: I agree with that.  Dr. Neeraj Agarwal: Jeanny, the last abstract I would like to mention before we wrap up the podcast is Abstract 4509, the results from the phase1 live SPARC 001 study. So, can you please tell us more about this study titled, “Phase-1 Live SPARC 001: The Study of Belzutifan in Advanced Solid Tumors,” which is an update of the renal cell carcinoma cohort with more than 3 years of total follow up?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. So, while the current therapeutic landscape for patients with metastatic clear cell renal cell carcinoma (RCC) has changed dramatically over the past several years, with significant improvement in patient outcomes. Most patients unfortunately still experience disease progression on current treatments.  So, in-depth molecular profiling of clear cell RCC has revealed recurrent loss of function mutations in VHL in actually greater than 90% of patients. So, the VHL protein, as you will recall, is part of the oxygen-sensing pathway, regulating levels of HIF which is hypoxia-inducible factor protein, it's a transcriptional activator that mediates the response to hypoxic conditions. So, HIF-2α is a key oncogenic driver in RCC.  So, previous data you may recall from the phase-1 Live SPARC 001 trial was designed to evaluate belzutifan so, this was a novel HIF-2α inhibitor which showed durable anti-tumor activity and acceptable safety profile in patients with metastatic clear cell RCC.  So, in Abstract 4509, Drs. Jonasch and Toni Choueiri presented updated results from this trial after more than 3 years of follow-up. Of the 55 patients enrolled 16% of patients remained in treatment. And 62% of patients had discontinued treatment because of, unfortunately, disease progression.  The median progression-free survival (PFS) for the total cohort was 14.5 months. And the overall disease control rate was 80%. Forty percent of patients experienced grade 3 treatment-related adverse events with the most frequent ones being anemia and hypoxia.  There were no great 4 or 5 treatment-related adverse events. And these results, therefore, show that belzutifan monotherapy continues to show a high rate of disease control and a safety profile in a heavily treated population of patients with metastatic RCC. So, it is great to see that there were no new safety signals.  Dr. Neeraj Agarwal: Very nice data indeed. So, Jeanny, what is the key takeaway message here for our listeners?  Dr. Jeanny Aragon-Ching: Yeah, I think the message here is that the use of belzutifan monotherapy continues to show efficacy and safety in patients with metastatic clear cell RCC, which have progressed on multiple prior contemporary therapies, and there are phase 3 trials currently underway.  Dr. Neeraj Agarwal: Jeanny, any final thoughts before we wrap up the podcast today?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. I think it's a really exciting time to be in genitourinary (GU) oncology, and I'm truly looking forward to seeing some great sessions at the 2022 ASCO Annual Meeting.  Dr. Neeraj Agarwal: Thank you, Jeanny, for sharing your insight with us today. It was a great conversation. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis  Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb , Astellas/Seattle Genetics  Travel, Accommodations, Expenses: Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, Astellas Pharma  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 expressed their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.       

Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about the first study to examine the quality of diagnosis and treatment of breast cancer in sex and gender minority patients and other key studies on disparities associated with access to clinical trials and rising drug costs.  Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast.  I'm delighted to welcome my friend and colleague Dr. Neeraj Agarwal, the director of the Genitourinary Cancers Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal also serves as editor-in-chief of the ASCO Daily News.  Today, he'll be sharing his insights on compelling studies that will be featured at the 2022 ASCO Annual Meeting, addressing access to clinical trials, disparities associated with high deductible health plans, rising drug costs, and more.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Neeraj, it's great to have you back on the podcast.  Dr. Neeraj Agarwal: Thanks, John.  Dr. John Sweetenham: Neeraj, let's begin with Abstract 6503. This study looks at the impacts of high deductible health plans on delays in metastatic cancer diagnosis. What do you think about this study and why should it be on our radar?  Dr. Neeraj Agarwal: Well, John, in high deductible health plans, patients are liable for the cost of all cancer-related care, with the exception of screening tests, until their annual deductible is met. Due to increased out-of-pocket costs, patients may postpone seeing a physician for concerning symptoms or diagnostic testing, leading to delayed diagnosis.  So, in this study, Mr. Nicholas Trad and J. Frank Wharam assessed the impact of high deductible health plans on the timing of metastatic cancer detection.  The authors leveraged a nationally representative cohort of more than 340,000 privately insured members whose employers mandated a switch from a low deductible of less than $500 plan to a high deductible plan of more than $1,000.  So, the group consisted of more than 1 million individuals in a contemporary time frame, whose employers offered only low deductible plans. Participants were matched based on multiple baseline characteristics, time to metastatic cancer diagnosis, and the before and after switching to high deductible health plans was investigated using a weighted Cox proportional-hazards model.  After matching, there were no systematic differences between the 2 groups with regards to baseline characteristics, and there were no differences in time to metastatic cancer diagnosis prior to the switch to high deductible health plans.  However, after the employer-mandated switch to the high deductible health plans, these participants had lower odds of metastatic cancer diagnosis, which was significant, statistically speaking, and indicates delayed detection of metastatic cancer diagnosis relative to the control group.  Dr. John Sweetenham: This is certainly concerning data, Neeraj. What's your key takeaway from this study?  Dr. Neeraj Agarwal: So, the key takeaway from the study is that compared with conventional health plans, high deductible health plans are associated with delayed detection of metastatic cancer, implying that patients postpone seeking care for concerning symptoms or even defer diagnostic testing when they're exposed to high-cost sharing.  Dr. John Sweetenham: Thanks, Neeraj. So, let's continue with this theme of the financial burden of cancer care for our patients. Of course, we're all aware of the rising costs of targeted oral therapies, and this was addressed in Abstract 6504, where the study looks at the rising costs of targeted oral treatments among Medicare beneficiaries. And the study reported a substantial increase in the total cost and out-of-pocket costs of these medicines. Can you tell us more about this abstract?  Dr. Neeraj Agarwal: Yes! So, due to the rapidly rising cost of targeted oral anticancer medicines, Drs. Meng Li and Ya-Chen T. Shih examined recent trends and the financial burden of these oral medicines among patients with cancer with Medicare Part D insurance. So, eligible patients in the SEER-Medicare database had to be 65 years and older and had to have one primary cancer diagnosis.  The investigators estimated the trends in the share of patients who used targeted oral anticancer medicines, the percentage of users reaching catastrophic coverage, and the total and patient out-of-pocket spending on these medicines in the catastrophic phase in a year.  So, from 2011 to 2016, the uptake of these oral anti-cancer medicines increased from approximately 4% to 9%. The percentage of those who reached catastrophic coverage increased from 55% to 60%.  Among those who reached the catastrophic phase, the mean total annual gross spending on oral anti-cancer medicine increased 4-fold from approximately $16,000 to $64,000. And the mean out-of-pocket spending for the patients rose from approximately $600 to $2600.  Dr. John Sweetenham: Yes, this is more evidence that the financial toxicity generated from an increase in spending and out-of-pocket costs is going to have serious impacts on our patients. Would you agree with that, Neeraj?  Dr. Neeraj Agarwal: Yes, John. The key takeaway from this study is that the financial burden of these oral anti-cancer medicines continues to increase. In the relatively short period of time, we see here, 5 years from 2011 to 2016, there was a 4-fold increase in the total cost and out-of-pocket cost of these medicines. And in my view, these findings warrant immediate actions to rein in drug prices and cap out-of-pocket spending for our patients.  Dr. John Sweetenham: Absolutely. It's very difficult to know where this will end unless we see some kind of slowdown in these rising costs. I'm going to change gears just a little bit now to address the access to clinical trials, which is the subject of Abstract 6505.  This study looks at the implementation of the Affordable Care Act Medicaid expansion, which was associated with an almost threefold increase in the proportion of patients using Medicaid in cancer clinical trials by early 2020. What are your thoughts on this study?  Dr. Neeraj Agarwal: As you said, the Affordable Care Act Medicaid expansion resulted in increased use of this platform across the nation. However, its impact on access to clinical trials has not been examined.  So, in this study, Dr. Joseph Unger and Dr. Dawn Hershman examined the number and proportion of patients insured by Medicaid at enrollment over time using data from the SWOG Cancer Research Network.  In addition, they also examined all patients, 18 to 64 years old, enrolled in treatment trials between 1992 to 2020 using Medicaid versus private insurance.  So, the implementation of the Affordable Care Act Medicaid expansion was associated with a nearly threefold increase from 7% to 21% in the proportion of patients using Medicaid in cancer clinical trials by early 2020.  The increase per year of Medicaid uses for patients in these treatment trials from states that implemented the Affordable Care Act Medicaid expansion was 27% compared to 7% for patients from other states who did not implement this platform of Affordable Care Act Medicaid expansion.  So, the key takeaway from the study is that better access to clinical trials for more vulnerable patients is critical to improving confidence in how generalizable these trial findings are. In addition, these results suggest that the recently enacted Cancer Treatment Act may continue to improve access to clinical trials for those with Medicaid insurance or those who are vulnerable patients.  Dr. John Sweetenham: Yes, I think this is a really important study which adds to the growing literature on the benefits of the Affordable Care Act and Medicaid expansion on cancer care in general, in this case, specifically related to clinical trials. So, so important, I think.  On that theme of equity, I think the next 2 abstracts we're going to discuss address specific aspects of equity, which I think are both interesting and really important. So, Abstract 6510 has interesting research which conveys an urgent need to ensure equitable patient-reported access and implementation and to address the greater reported symptom burden among minority patients. Why do you think this study is important?  Dr. Neeraj Agarwal: The routine collection of patient-reported outcomes for patients with cancer is an evidence-based practice and a critical component of high-quality cancer care, but the real-world adherence and reporting patterns are poorly understood.  In this study, Dr. Samuel Takvorian and Dr. Ravi Parikh examined differences in adherence to the collection of patient-reported outcomes and reported symptoms by race and ethnicity.  This was a retrospective cross-sectional study using de-identified electronic health record data from an National Cancer Institute (NCI)-designated Comprehensive Cancer Center. The participants included adults seen in follow-up at 1 of the 2 medical oncology practices—one was in academics and one was in the community—from June 2019 to February 2020. Using ordinary least-squares regression, the authors modeled patient adherence as a function of race or ethnicity, and this was adjusted for age, sex, insurance, median area income, ECOG, performance status, and many other patient-related characteristics.  The results show that adjusted mean PRO adherence and reported symptoms varied by race and ethnicity, with Black and Hispanic patients being less likely to complete PRO questionnaires, but reporting significantly higher symptom burden compared to the White patients.  Dr. John Sweetenham: Right. So, it seems that more work is needed to ensure equitable access and adherence to PRO questionnaires so we can better address the symptom burden of our minority patients.  Dr. Neeraj Agarwal: Correct, John. In this large cohort reflecting real-world PRO collection patterns, Black and Hispanic patients were less likely than White patients to complete these PRO questionnaires, but more likely to report more severe symptoms. And I think there is an urgent need to ensure equitable PRO access and implementation and to address the greater reported symptom burden among minority patients.  Dr. John Sweetenham: Let's continue the theme of health equity and cancer care equity into the use of telemedicine. Of course, we saw a massive expansion of telemedicine for patients with cancer during the COVID-19 pandemic.  But studies are emerging now to show that there have been substantial disparities among the Black, uninsured, non-urban, and less affluent patients who are less likely to use telemedicine services.  Abstract 6511 reminds us that telemedicine may expand access to specialty care, but the proliferation of these services may widen cancer care disparities if vulnerable populations don't have equitable access. Can you tell us more about this abstract?  Dr. Neeraj Agarwal: These are indeed very interesting findings, John. The COVID-19 pandemic was associated with declines in in-person clinical visits, with a concurrent increase in the use of telemedicine.  In this study, Dr. Gregory S. Calip assessed demographic and socioeconomic factors associated with telemedicine use among patients initiating treatment for 21 common cancers at community oncology clinics.  This was a retrospective study and made use of the nationwide Flatiron electronic health record derived de-identified database of patients with cancer. The authors focused on differences in telemedicine use across race and ethnicity, insurance coverage, rural versus urban areas, and socioeconomic status.  They used logistic regression models for this analysis, which was adjusted for clinical characteristics to examine differences in telemedicine use among these different cohorts.  Results indicate Black patients were significantly less likely to use telemedicine services compared to White patients. Telemedicine use was also significantly lower among patients without documented insurance than well-insured patients. It was also lower in patients from rural and suburban areas versus patients who were living in urban areas. Lastly, telemedicine use was significantly lower in patients in the least affluent areas than those in the most affluent areas.  So, during the COVID-19 pandemic, nearly one-fifth of patients initiating cancer treatment using telemedicine services—among these patients, we see substantial disparities. So, Black, uninsured, non-urban, and less affluent patients were less likely to use telemedicine services.  So, the take home message from this study is that while telemedicine may expand access to care, the proliferation of these services may actually widen cancer care disparities if vulnerable populations do not have equitable access to these services.  Dr. John Sweetenham: Thanks, Neeraj. So, the final study that we'll discuss today also looks at another aspect of disparities, and that's Abstract 6517. It's a case-controlled study of health care disparities in sex and gender minority patients with breast cancer. What are the key takeaways from this study?  Dr. Neeraj Agarwal: Disparities and the quality of diagnosis and treatment of breast cancer in sex and gender minority populations are largely undefined. Only 24% of studies funded by the National Cancer Institute capture data on sexual orientation and only 10% capture data on gender identity.  In this case-control study, Drs. Eric Eckhert and Allison W. Kurian matched sex and gender minority patients with breast cancer to cisgender heterosexual controls in the Stanford University health care database. Ninety-two sex and gender minority patients were identified who were then matched by year of diagnosis, age, stage of cancer, presence of estrogen receptor (ER), and HER-2/neu receptor status to cisgender heterosexual controls within this database.  Additional data on demographics, diagnosis, treatment, and relapse were then manually abstracted from the electronic health care records. The sex and gender minority cohort were comprised of 80% lesbians, 13% bisexuals, and 6% transgender men.  One of the most pertinent findings was a significant, almost twice as much delay in time to diagnosis from the onset of symptoms in these minority patients versus control. Although there was no difference in the receipt of surgery or surgical radiation or new adjuvant therapy, sex, and gender minority patients were significantly less likely to undergo chest reconstruction surgery, and if they were estrogen receptor-positive, they were significantly less likely to complete at least 5 years of ER directed therapy.  Please also note that sex and gender minority patients used more alternative medicine, had a higher rate of documented refusal of recommended oncology treatments, and they experienced a higher recurrence rate.  So, the key takeaway from this study is that—this is the first study, I really want to congratulate the investigators who examined the quality of diagnosis and treatment of breast cancer in sex and gender minority patients. Several novel potential health care disparities are identified in these patients, which should be further evaluated in population-based studies to inform further interventions.  Dr. John Sweetenham: Neeraj, it's always a pleasure to talk with you and have an opportunity to spend some time with you. Thanks very much for sharing your insights on these compelling studies today. Our listeners will find the links to these abstracts in the transcripts of this episode.  Dr. Neeraj Agarwal: Thanks, John.  Dr. John Sweetenham: And thanks to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham  Consulting or Advisory Role: EMA Wellness  Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas     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. 

ECog 057 Track ListTwisted Hearts (Robbie Seed)Sky Falls Down (Ocean Lab)I Remember You (Stargazers)Wild Gods (Kenny Palmer)Equalizer (Shugz)Steam (Daniel Skyver)Leave You Now (Allen Watts)Believe in You (Maria Healy)Occult (Alan Sharkey)Switch Up (Dustin Husain)Over You (Lost Witness)Take Me Up (David Forbes)Quantum Eraser (Craig Connelly)Satellite (Oceanlab)Send Your Love (Glaciel Storm)The New Colossus (FAWZY)Ultimate (Rene Ablaze)

FDA 批准新型的核输出蛋白抑制剂用于治疗多发性骨髓瘤和弥漫大B细胞淋巴瘤LANCET 利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤Blood DIC时常出现的新型的凝血机制塞利尼索（selinexor）塞利尼索（selinexor）一种口服选择性核输出蛋白抑制剂，2019年被FDA批准上市用于治疗复发或难治性多发性骨髓瘤；2020年7月，适应症扩展到弥漫大B细胞淋巴瘤。《口服塞利尼索-地塞米松治疗三重难治性多发性骨髓瘤》 New England Journal of Medicine，2019年8月 (1)研究旨在评价塞利尼索对三重难治性多发性骨髓瘤的疗效和安全性。纳入122名、中位年龄65岁、至少一种蛋白酶体抑制剂、一种免疫调节剂和达雷木单抗耐药的、多发性骨髓瘤患者。给予每周两次口服塞利尼索80mg+地塞米松20mg治疗。26%的患者出现部分或更好的缓解，2名患者完全缓解；39%的患者轻微缓解或有所好转。中位缓解时间为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。血小板减少是常见的严重不良反应。结论：塞利尼索-地塞米松使现有治疗方法难以治愈的骨髓瘤患者延长了生存期。《SADAL研究：塞利尼索（selinexor） 在复发或难治性弥漫性大B细胞淋巴瘤患者中的应用》Lancet Haematology，2020年7月 (2)SADAL研究的目的是评估单药塞利尼索对复发或难治性弥漫大B淋巴瘤患者的疗效这项多中心、跨国、开放标签的2b期研究，纳入已经接受了2 - 5种治疗、自体干细胞移植后或不适合进行自体干细胞移植的、复发难治性弥漫大B细胞淋巴瘤患者共267人，随机接受塞利尼索60mg和塞利尼索100mg治疗，研究中期100mg剂量被终止。塞利尼索的总有效率为28%，12%的患者完全缓解，17%的患者部分缓解。最常见的3-4级不良事件是血小板减少、中性粒细胞减少、贫血等。最常见的严重不良事件是发热、肺炎和脓毒症。结论：塞利尼索单药治疗复发或难治性弥漫大B患者有一定的疗效，且不良事件可控制的。弥漫性大B细胞淋巴瘤弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，占25%。最常见的症状为颈部或腹部淋巴结肿大，约30%的患者出现全身性症状（发热、体重减轻、盗汗）。骨髓受累和结外髓外病变的发生率在30%和40%。弥漫大B细胞淋巴瘤的肿瘤细胞通常广泛表达B细胞抗原（CD19、CD20、CD22和CD79a）。《XPO1的表达会恶化不利的弥漫大B细胞的预后，而在没有p53突变体的情况下，塞利尼索可以有效地靶向该细胞》Journal of Hematology Oncology，2020年11月 (3)XPO1抑制剂塞利尼索（selinexor）最近被批准用于复发/难治性的弥漫大B细胞淋巴瘤，研究的目的是评价XPO1对患者的预后影响以及高危患者的合理联合治疗方案。来自厦门大学医学院的研究人员发现XPO1高表达的544例患者，均出现显著的预后不良的情况，尤其是在BCL2过表达的患者中。通过对30个、具有不同分子和遗传背景的弥漫大B细胞淋巴瘤的、细胞株进行研究后发现，塞利尼索具有很强的细胞毒性，特别是在BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤（HGBCL-DH）中。然而，p53基因突变显著降低了塞利尼索在整个细胞系、以及BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中的细胞毒性。塞利尼索联合BET抑制剂INCB057643对MYC/BCL2双重打击的、高级别B细胞淋巴瘤的治疗效果显著增强，克服了p53基因突变的耐药性。结论：XPO1降低了BCL2过表达和双重打击等预后不良因素的、弥漫大B细胞淋巴瘤患者的生存，这与塞利尼索在这两个细胞系中显示出的更好的疗效是一致的。在MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中，联合使用INCB057643处理，可以克服p53基因突变导致的塞利尼索耐药的情况。《弥漫性大B细胞淋巴瘤的国际预后指标：IPI、R-IPI和NCCN-IPI的比较》Blood，2020年6月 (4)弥漫大B细胞淋巴瘤的患者生存率存在很大的异质性。目前临床上常用的预后评分系统包括：国际预后指数（IPI）、修订的IPI（R-IPI）和国家综合癌症网络IPI（NCCN-IPI）。这三种评分系统纳入一些简单临床参数（年龄、乳酸脱氢酶、受累个数/部位、分期、表现状态）。研究人员近20年来，接受利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和强的松治疗的2124例患者的数据用于评估哪个评分系统能最准确的预测生存率。使用IPI、R-IPI和NCCN-IPI的5年生存率估计分别为54%至88%、61%至93%和49%至92%；三组评分的一致性指数分别为0.626、0.59和0.632。NCCN-IPI在高风险、低风险和生存期评价方面都表现更高；而且NCCN-IPI风险类别与生存期显著相关(P≤.01)。结论：NCCN-IPI的预测准确性较高，NCCN-IPI低风险的患者的生存结果良好，但如果能将肿瘤的分子特征和微环境特征整合到NCCN-IPI或IPI中，可能将提高其准确性。弥漫性大B细胞淋巴瘤的治疗初始标准治疗是联合化疗（如CHOP方案，环磷酰胺、多柔比星、长春新碱和泼尼松）+抗CD20单抗（利妥昔单抗），即R-CHOP方案。复发难治性弥漫大B细胞淋巴瘤首选自体干细胞移植。治疗进展：2017年，FDA批准Axicabtagene ciloleucel（商品名Yescarta，一种自体抗CD19嵌合抗原受体CAR-T细胞疗法）治疗复发难治性弥漫大B细胞淋巴瘤。《回顾性研究：R-CHOP方案治疗原发性纵隔大B细胞淋巴瘤》Blood，2020年6月 (5)原发性纵隔大B细胞淋巴瘤的治愈率随着利妥昔单抗的结合而提高；然而，放射治疗的作用仍不明确。2005年之前，通常建议患者接受R-CHOP方案放疗；2005年之后，只有治疗结束后PET扫描呈阳性的人才接受放疗。文章回顾性的分析了共159例患者，总体的5年生存期为89%，在不同的治疗时期相似，总体来说只有10%是难治性的。2005年后，共有113例患者进行了PET扫描，其中63%阴性，37%阳性，5年生存率为97%对88%。对于PET扫描评分较高的患者，预后也较差。结论：经R-CHOP治疗的纵隔弥漫大B淋巴瘤患者的结果是良好的，使用PET评估决定是否放疗减少了不必要的放疗。《HOVON-84研究：利妥昔单抗联合早期利妥昔单抗强化治疗弥漫性大b细胞淋巴瘤的3期临床研究》Journal of Clinical Oncology，2020年10月(6)该研究的目的是评估了R-CHOP方案的、前4个周期早期、强化利妥昔单抗治疗与标准R-CHOP方案比相比是否能改善预后。研究纳入574例、弥漫大B细胞淋巴瘤的患者，给予6个或8个周期的R-CHOP-14方案治疗，随机早期强化利妥昔单抗治疗（RR-CHOP-14方案）或不强化治疗（R-CHOP-14）。R-CHOP-14组和RR-CHOP-14组的、诱导期完全缓解率分别为89%和86%。中位随访92个月后，R-CHOP-14组和RR-CHOP-14组的、3年无进展生存率分别为74%和71%（P = 0. 15），两组总生存率分别为81%和76%（P=0.09）。在RR-CHOP-14组中，年龄在66岁至80岁的患者在前4个周期中经历了明显更多的不良事件，特别是中性粒细胞减少和感染。结论：RR-CHOP-14（在R-CHOP-14基础上早期强化使用利妥昔单抗）不能改善未经治疗的弥漫大B细胞淋巴瘤患者的疗效。Burkitt淋巴瘤Burkitt淋巴瘤是一种高度侵袭性的B细胞肿瘤，目前识别出3种不同的临床形式：地方性Burkitt淋巴瘤、散发性Burkitt淋巴瘤和免疫缺陷相关性Burkitt淋巴瘤。虽然流行病学、临床表现和遗传学特征有所不同，但是组织学上相同，并具有相似的临床行为，因此通常采用相似的方法治疗。对于大多数Burkitt淋巴瘤的成人患者，通常建议选择强化短程联合化疗，或者急性淋巴细胞白血病样的诱导+巩固+维持治疗，无法耐受的患者使用剂量调整的EPOCH化疗方案（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）。近年来的一个的热点是在化疗基础上加用利妥昔单抗（抗CD20单抗）。《随机对照研究：使用风险适应性的、剂量调整的DA-EPOCH-R方案治疗Burkitt淋巴瘤》Journal of Clinical Oncology，2020年8月(7)研究的目的是评价，经剂量调整的（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）联合利妥昔单抗（DA-EPOCH-R方案）治疗Burkitt淋巴瘤的疗效。研究纳入113名未接受过治疗的Burkitt淋巴瘤患者，中位年龄49岁，25%HIV阳性，低风险患者接受了无中枢神经系统预防的、3个周期的治疗；高风险患者接受了6个周期的治疗、以及鞘内治疗。中位随访58.7个月，低危患者无进展生存率和总生存率分别为84.5%和87.0%；高危患者无进展生存率和总生存率分别为82.1%和100%和。治疗对不同年龄组、HIV阳性和各风险组都同样有效。疾病累及脑脊液的、高危患者中，药物毒性相关的死亡或治疗失败的风险最大。5例治疗相关死亡发生在治疗期间，发热性中性粒细胞减少发生在16%的周期中，肿瘤溶解综合征是罕见的。结论：DA-EPOCH-R方案治疗对成人Burkitt淋巴瘤有效，且耐受良好，无论年龄或HIV状态如何。但疾病脑脊液的患者的治疗方案仍需商榷。《开放标签对照研究：利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤的3期临床研究》Lancet，2016年6月(8)这项随机、对照、开放标签的3期临床试验中，招募了45个中心的、>18岁的、新诊断的、HIV阴性的Burkitt淋巴瘤患者。分为B组（无骨髓或中枢神经系统受累）和C组（有骨髓或中枢神经系统受累）。治疗方案为利妥昔单抗+LMB方案化疗，以及单独LMB方案化疗。共纳入260例患者，中位随访38个月。利妥昔单抗组3年无事件生存率75%，显著优于单独化疗组；不良事件在两个治疗组之间没有差异，最常见的是感染和中性粒细胞减少。结论：在短期强化化疗方案中加入利妥昔单抗可以改善成人Burkitt淋巴瘤的无事件生存率。 《队列研究：美国30个癌症中心的、真实世界的、Burkitt淋巴瘤的治疗结果与进展》Blood，2020年7月(9)研究人员对2009年至2018年的、美国30个癌症中心的、未经治疗的Burtkitt淋巴瘤的成人患者进行了分析。研究人员分析了641例Burkitt淋巴瘤患者基线特征包括：中位年龄47岁；HIV阳性 占22%；23%的患者ECOG生活质量评分 2-4分；42%患者有>1个淋巴结外病灶；晚期78%；中枢神经系统受累19%；治疗相关死亡率为10%，最常见的原因是败血症、胃肠道出血、穿孔和呼吸衰竭。在45个月的中位随访中，3年的无进展生存率和总生存率分别为64%和70%，这与是否为HIV阳性无关。接受利妥昔单抗治疗的患者生存率更更高（3年无进展生存率为为67%比38%；总生存率为72%比44%），这与是否住院治疗无关。在学术中心治疗的患者和在社区中心治疗的患者的结果也有所改善（3年无进展生存率为67%比46%；总生存率72%比53%)。多变量模型中，预测生存率较短的因素包括：年龄≥40岁、ECOG生活质量评分2-4分、乳酸脱氢酶>3xULN和中枢神经系统受累；而且，以上因素越多，生存率越低生存率。结论：真实世界的分析中，成人Burkitt淋巴瘤的临床预后比临床研究的结果更温和。此外，疾病诊断时确定的预后相关的因素可以帮助评估真实的预后。新型的DIC中由组蛋白启动的替代凝血酶通路《基础研究：弥散性血管内凝血中，由细胞外组蛋白启动的替代凝血酶通路》Blood，2020年7月 (10)凝血酶的产生、活化对弥散性血管内凝血（DIC）的病理发展都至关重要。通常，凝血酶由凝血酶原复合物产生，包括活化的X因子（FXa）、活化的辅助V因子（FVa）和磷脂（钙离子存在的情况下清除凝血酶）。在危重症中，广泛的细胞损伤可释放组蛋白进入循环，增加凝血酶的生成，引起DIC，但其分子机制尚不清楚。在本研究中，来自利物浦大学的研究人员发现：在有组蛋白，但是没有活化的辅助V因子和磷脂的情况下，机体也能形成一种替代的凝血酶。组蛋白可以直接结合凝血酶原片段F1和F2，促进X因子裂解凝血酶原、释放凝血酶，而不需要磷脂参与。小鼠体内输注组蛋白可诱导产生DIC；但如果事先输注凝血酶原F1+F2片段，再输注组蛋白则显著降低DIC出现的可能性。在重症监护病房脓毒症患者中（n=144），DIC患者的循环组蛋白水平显著升高。这些数据均表明，组蛋白诱导的替代凝血酶可诱导血管内凝血，并揭示了凝血酶产生和DIC发展的新的分子机制。此外，在这个凝血机制中，组蛋白使X因子的需求显著减少，即使VIII因子和IX缺乏的小鼠中，也能形成血栓。结论：本研究揭示了一种具有治疗潜力的、新型的凝血机制，既可以激活全身凝血功能，又可以纠正凝血因子缺陷导致的凝血功能障碍。《COVID-19及其对血栓和抗凝的影响》Blood，2020年6月 (11)COVID-19引起的严重感染可能与凝血功能障碍有关，这在感染引起的弥散性血管内凝血功能障碍（DIC）患者中观察到的炎症变化很相似。肺是COVID-19的靶器官，患者急性肺损伤可发展为呼吸衰竭，也可发生多器官衰竭。COVID-19的初始凝血病变表现为D-二聚体和纤维蛋白/纤维蛋白原降解产物显著升高，而凝血酶原时间、部分凝血酶时间和血小板数量异常相对少见。故建议对患者进行凝血功能筛查，包括测定D-二聚体和纤维蛋白原水平。治疗上，应像对待任何危重病人一样管理，遵循对危重病人采用的血栓栓塞预防、和对脓毒症引起DIC的患者采用标准支持治疗。虽然D-二聚体、脓毒症生理学和消耗性凝血障碍是死亡的预测因子，但目前的数据不建议使用足量抗凝。尽管COVID-19相关的凝血功能障碍，但出血时间尚未见报道。如果确实发生出血，应遵循DIC和出血管理的标准指南。《回顾性观察队列研究：COVID-19患者出院后的血栓和出血时间》Blood，2020年8月 (12)COVID-19肺炎与血栓前状态相关，住院期间血栓事件发生率高；然而，出院后血栓形成的数据有限。研究人员对未接受抗凝治疗的COVID-19出院患者进行了回顾性观察队列研究。该队列包括163名患者，平均随访30天，平均住院时间为6天， 26%需要重症监护。出院后第30天血栓累积发生率（包括动脉和静脉事件）为2.5%；单纯静脉血栓栓塞发生率为0.6%；大出血发生率为0.7%，非大出血发生率为2.9%。因此，COVID-19患者出院后血栓形成率和出血率似乎相似，这强调需要更多的研究来提供全面的、出院后的血栓预防建议。参考文献1.Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-38.2.Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e22.3.Deng M, Zhang M, Xu-Monette ZY, Pham LV, Tzankov A, Visco C, et al. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53. J Hematol Oncol. 2020;13(1):148.4.Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041-8.5.Hayden A, Tonseth P, Lee DG, Villa D, Gerrie AS, Scott DW, et al. Outcome of Primary Mediastinal Large B-cell Lymphoma Using R-CHOP: Impact of a PET Adapted Approach. Blood. 2020.6.Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, et al. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020;38(29):3377-87.7.Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, et al. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol. 2020;38(22):2519-29.8.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10036):2402-11.9.Evens AM, Danilov AV, Jagadeesh D, Sperling AL, Kim SH, Vaca RA, et al. Burkitt Lymphoma in the Modern Era: Real World Outcomes and Prognostication Across 30 US Cancer Centers. 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Hi friends! Sorry for the delay on this episode — Maansi and I were scrambling at the end of the semester to get stuff done.It's just us this time, and we are talking about something that is at the core of neuroscientific research — how the heck do we record data from the brain? Turns out there are a bunch of different ways, and each has its own pros and cons. Maansi and I give you the scoop.Thanks as always to Riohso for our intro and outro music: https://soundcloud.com/riohsoFollow us on Twitter: https://twitter.com/brainwaves_castGot questions? Want to be on the cast? Send us an email at brainwaves.neurocomm [at] gmail.com

In this episode, Maansi and Garret are joined by none other than Liberty Hamilton! Dr. Hamilton is a computational neuroscientist who studies the neurophysiology of speech and language through an invasive procedure known as electrocorticography (A.K.A., ECoG). Oh, and she's also our boss!