Stoosmačtyřicátý díl seriálu, který každý měsíc mapuje to nejzajímavější, co se událo v kosmonautice. Obsah dílu: 0:00 - Představení témat 1:36 - Start Dalekohledu Jamese Webba 8:22 - Start teleskopu IXPE 10:37 - Start zásobovací mise CRS-24 14:02 - Start turistické mise Sojuz MS-20 17:10 - Kosmonautika v kostce 28:51 - Detaily o raketě Neutron 31:06 - Výstup z ISS do volného prostoru 32:43 - Start mise Türksat 5B 34:44 - Start dvou mise Starlink 37:20 - Závěrečné shrnutí a výhled na další měsíc
Under criminal law, a principal is any actor who is primarily responsible for a criminal offense. Such an actor is distinguished from others who may also be subject to criminal liability as accomplices, accessories or conspirators. The legal principle of vicarious liability applies to hold one person liable for the actions of another when engaged in some form of joint or collective activity. History. Before the emergence of states which could bear the high costs of maintaining national policing and impartial court systems, local communities operated self-help systems to keep the peace and to enforce contracts. Until the thirteenth century, one of the institutions that emerged was an involuntary collective responsibility for the actions committed by one of the groups. This was formalized into the community responsibility system (CRS) which was enforced by a fear of loss of community reputation and of retaliation by the injured community if the appropriate compensation was not paid. In some countries where the political system supported it, collective responsibility was gradually phased out in favor of individual responsibility. In Germany and Italy, collective systems were in operation as late as the sixteenth century. While communities were relatively small and homogeneous, CRS could work well, but as populations increased and merchants began to trade across ever wider territories, the system failed to match the emerging societies' needs for more personal accountability and responsibility. In England, Henry the 1st allowed London to opt out of the CRS and to appoint a sheriff and justices in 1133, and between 1225 and 1232, Henry the 3rd assured the merchants of Ypres that none of them "will be detained in England nor will they be partitions for another's debts". Nevertheless, the idea of imposing liability on another despite a lack of culpability never really disappeared and courts have developed the principle that an employer can incur liability for the acts and omissions of an employee if committed by the employee in the course of employment and if the employer has the right to control the way in which the employee carries out his or her duties (respondeat superior). The imposition of vicarious liability in these circumstances has been justified on the following grounds: Exercise of control: If penalties are serious enough, it is assumed that rational employers will take steps to ensure that employees avoid injuring third parties. On the other hand, rational employers may choose to rely on independent contractors for risky operations and processes. Risk spreading: Many consider it socially preferable to impose the cost of an action on a person connected to it, even if a degree removed, rather than on the person who suffered injury or loss. This principle is also sometimes known as the "deep pocket" justification. Internalizing the social costs of activities: The employer usually (though not always) passes on the cost of compensating injury or loss to the customers and clients. As a result, the private cost of the product or service will better reflect its social cost. These justifications may work against one another. For example, insurance will increase the ability to do risk spreading, but will reduce incentives for the exercise of control. --- Send in a voice message: https://anchor.fm/law-school/message Support this podcast: https://anchor.fm/law-school/support
La 25e édition de 2x Noël a lieu du 24 décembre 2021 au 11 janvier 2022. Pendant toute la durée de l'action, vous pouvez déposer vos colis, sans adresse mais munis de la mention "2x Noël, au guichet de poste le plus proche. Ils seront acheminés gratuitement à la Croix-Rouge suisse. L'autre possibilité est de se rendre sur le site de l'action: www.2xnoel.ch et d'y acheter directement un colis en ligne. Les dons générés par les colis en ligne bénéficient aux plus démunis en Arménie, en Moldavie, au Kirghizistan et en Bosnie-Herzégovine et servent principalement à financer les secours d'hiver. Dans le cadre de ce dispositif, la Croix-Rouge vient en aide à des gens en situation de précarité particulièrement exposés au froid. Elle distribue des colis alimentaires et des repas chauds et verse des contributions financières pour que ces personnes puissent s'acheter du bois ou encore des médicaments. L'argent récolté via les colis en ligne permet d'acheter nourriture et biens de première nécessité sur les marchés locaux en Arménie, en Bosnie-Herzégovine, en Moldavie et au Kirghizistan. En Arménie par exemple, les hivers sont rudes et longs. Nombres de personnes âgées vivent dans le plus grand dénuement. Grâce aux dons collectés par 2x Noël, elles bénéficient d'une aide alimentaire régulière tout l'hiver. "Les aînés subissent de plein fouet la pauvreté, explique Jina Sargizova, déléguée CRS en Arménie. L'électricité est hors de prix. Souvent, ils doivent choisir entre se chauffer ou manger"
RJ Curtis, former past president of Country Radio Seminar (CRS) joins us in the studio. After being forced to take a year off due to the pandemic and having to go virtual, the Country Radio Broadcasters Association announces the return of in-person CRS which will be held on Feb. 23-25, 2022. RJ talks about what potential attendees should know about this year's event. The upcoming conference will focus on all aspects of the Country Radio business, providing information on how to be successful in this ever changing world. Whether you're a corporate radio conglomerate, an independent “Mom & Pop” radio station, a DSP, or internet radio, this conference is designed to help you make it thru the challenges and emerging trends in country radio and how they might impact artists and industry members. We also discuss the newly announced Lisa McKay Women In Radio Scholarship Program, a scholarship for young, female broadcasters created in honor of the late Lisa McKay, a radio veteran who fiercely championed young female broadcasters. Even if you're not into Country Music, this is still a vital, and informative topic of discussion regarding terrestrial radio, and how they're working to co-exist with satellite and other platforms. RJ Curtis is a 41-year Country radio/Music Row executive whose career has impacted nearly every aspect of the format. His resume features 30 years in major market radio (Los Angeles, Phoenix, San Antonio), where he served as Program Director, Operations Manager, Music Director, and on-air talent for iconic radio brands such as KNIX/Phoenix, KCYY/San Antonio and KZLA/Los Angeles, as well as the nationally syndicated “After Midnite” show. Curtis later spent 13 years providing insight, analysis, and commentary on the Country music industry while writing and reporting for Radio & Records Magazine, Billboard, Country Aircheck, and All Access Music Group. His experience includes time in the record industry, too, with Arista Nashville, as Dir./Regional Promotion. A 20-year CRB Board member and the organization's past President, VP, Secretary, and Treasurer, Curtis transitioned to his current role as CRB Executive Director in 2018. He has served on the Board of Directors of both ACM and CMA and has served on the St. Jude Children's Hospital Radio Advisory Board since 2015. The Business Side of Music ™ Lotta Dogs Productions LLC Co-Produced and Hosted (by the guy who has a face for podcasting): Bob Bender Co-Producer, Creator, and Technical Advisor (the man behind the curtain): Tom Sabella Director of Video and Continuity (the brains of the entire operation): Deborah Halle Audio/Video Editor Mark Sabella Midnight Express Studio Olian, NY Marketing and Social Media: Kaitlin Fritts Executive Assistant to Bob and Tom (the one who keeps us on track and our schedules straight) Tammy Kowalski All Around Problem Solver: Connie Ribas Recorded at: The Bunker in Franklin, TN (except during the Covid 19 pandemic, then it's pretty much done VIA Skype or over the phone, with the exception for those fearless enough to come to Bob Bender's living room… and there are a few). Mixed and Mastered at Music Dog Studios in Nashville, TN Production Sound Design: Keith Stark Voice Over and Promo: Lisa Fuson Special Thanks to Tom Sabella and Traci Snow for producing and hosting over 100 episodes of the original “Business Side of Music” podcast, and trusting us to carry on their legacy. Website: Sponsorship information Interview submission
Au programme de cette 53ème édition de la Contre-Matinale du Média, présentée ce vendredi 10 décembre par Nadiya Lazzouni : · La titrologie : Retrouvez la traditionnelle rubrique dans laquelle nous analysons les unes de la presse mainstream et revenons sur leur vision de l'agenda médiatique. Puis, un petit focus sur différents contenus proposés par nos camarades de la galaxie des médias indépendants et alternatifs. · Le système de santé cubain, le meilleur au monde ? : Le système de santé et la médecine cubaine sont-ils les meilleurs au monde ? Ce système de santé public, gratuit pour tous, hérité de la Révolution de 1959, s'exporte partout dans le monde, aussi bien dans les pays pauvres que dans les pays industrialisés du nord. Aujourd'hui même, Cuba fabrique ses propres vaccins contre la COVID-19, indépendamment des gros laboratoires pharmaceutiques globalisés, grâce à des laboratoires publics. Une souveraineté acquise malgré un embargo américain condamnant l'île à la pauvreté et au manque de ressources. A ce sujet, notre journaliste Irving Magi s'est entretenu avec Maïlys Khider, autrice de « Médecin cubains, les armées de la paix », paru aux éditions LGM. Extraits. · Trois ans après la mort de Zineb Redouane, tuée par un tir de grenade lacrymogène : À Marseille, samedi dernier, des centaines de personnes se sont retrouvées au Vieux Port pour rendre hommage à Zineb Redouane, décédée à la suite d'un tir de grenade lacrymogène de CRS le 2 décembre 2018 en marge d'une manifestation de gilets jaunes. Taha Bouhafs était présent à cette commémoration réprimée par la police. L'affaire n'est pas terminée, et les vérités sur cette affaire ne sont pas toutes à jour. Taha Bouhafs a rencontré l'avocat de la famille, Yassine Bouzrou. · La deuxième heure avec Cemil : Au matin du 8 décembre, à 7h45, deux personnes ont été agressées par une autre au parc de Bercy, à Paris. Jusque là, il pourrait s'agir d'un fait divers malheureusement pas si rare. Sauf que l'agresseur était armé d'un sabre et que ses deux victimes sont des exilés soudanais survivants dans un campement aux allures de bidonville. Il reçoit pour en parler Kerill Theurillat, Coordinateur Utopia 56 Paris. Vous pouvez retrouver la Contre-matinale en direct audio sur Mixlr : https://mixlr.com/le-media ▶ Soutenez Le Média :
This week we're talking about the balance as SpaceX is on red alert! Starship & the Raptor engine are at risk to bankrupt SpaceX if they don't figure it out soon. Elon's email to SpaceX employees was leaked and reveals what we have seen so many times from Musk - logical, almost Vulcan-like honesty. All of this was revealed as SpaceX continues to battle their competition like Blue Origin (just chosen for a contract to develop Orbital Reef to replace the ISS) and Rocket Lab (who revealed their design for their Neutron Rocket, which will compete with Falcon9!). While these companies duke it out for a share of the space economy, its a great time for space development as this type of healthy competition pushes us further towards sending the first woman and next man to the surface of the moon. And that's just the beginning of what's to come! Thank you for joining us 00:00 - Introduction/SpaceX on Red Alert! 03:35 - Blue Origin win's Space Station contract 07:00 - Rocket Lab's newest rocket - Neutron 14:00 - Elon musk emails & 'typical Elon' 20:00 - Starship SN20 getting ready down at Starbase 23:00 - Closing thoughts, how to support the podcast If you like what we are doing and want to support us, please subscribe to our SubStack (todayinspace.substack.com) and on the various platforms for the podcast. It's free for you and means so much for us! And don't forget to share with friends & family too. Listen/subscribe to the podcast on: Apple Podcasts & Spotify Watch/subscribe to the podcast & clips on: Youtube Spread Love, Spread Science. Alex G. Orphanos Links, References for this episode: Yusaku Maezawa launches to the ISS to train for trip around the moon: https://www-forbes-com.cdn.ampproject.org/c/s/www.forbes.com/sites/roberthart/2021/12/08/japanese-billionaire-yusaku-maezawa-turns-space-tourist-blasts-off-to-international-space-station-aboard-russian-craft/amp/ SpaceExplored article on SpaceX Raptor Crisis by Derek Wise: https://spaceexplored.com/2021/11/29/spacex-raptor-crisis/ Elon being honest about Tesla & SpaceX almost dying https://www.theverge.com/2015/5/14/8605597/elon-musk-discusses-spacex-tesla-near-bankruptcy Elon being honest about CRS-7 Flight Failure https://www.cbsnews.com/news/spacex-falcon-9-rocket-destroyed-in-launch-mishap/ Elon's other emails - https://www.ibtimes.com/spacex-boss-elon-musk-threatened-drastic-action-against-employees-who-use-unnecessary-1972972 NASA certifying that Crew Dragon is the only certified craft for humans to go to space/ISS https://www.businessinsider.com/spacex-awarded-three-more-commercial-crew-flights-nasa-boeing-2021-12?fbclid=IwAR350QUZJA-BjgzVTNThjAHeQRGBcvLAznuQ-lqUuaXQRkL-wPt3TTPT5bk Fairing recovery: Rocket lab vs SpaceX: https://www.rocketlabusa.com/launch/neutron/ Blue origin: Orbital Reef gets chosen by NASA https://www.blueorigin.com/news/nasa-selects-orbital-reef-for-space-station-replacement 00:00 - Introduction/SpaceX on Red Alert! 03:35 - Blue Origin win's Space Station contract 07:00 - Rocket Lab's newest rocket - Neutron 14:00 - Elon musk emails & 'typical Elon' 20:00 - Starship SN20 getting ready down at Starbase 23:00 - Closing thoughts, how to support the podcast
We have borne witness in the last several years to a troubling trend—high-profile, deadly shootings that often involve law enforcement or get captured in real-time on video and spread via social media. In those situations, the communities in which the shootings occur often feel like they're coming apart at the seams. That's where mediators from the Community Relations Service often come in—quietly, without much fanfare—to help communities heal. Grande Lum, former director of the Community Relations Service and the author of a book on the CRS, joined the podcast to chat about his work.
On this Thanksgiving Episode of FTCUTD, Greggo and Skye are joined by Cultureverse member Kaiya McCollough, having linked up over the weekend in Louvegas, we recap our trip covering the NWSL Championship between Chicago Red Stars and the Washington Spirit, which saw Washington grab their first NWSL title off the maestro performance from Trinity Rodman. We go thru our experiences in the city, meeting colleagues we've come in contact with on social media, and the vibes felt thru the weekend. But good things don't last long, as news broke late Sunday night that Chicago Head Coach Rory Dames resigned, shortly before a major story broke that Dames was the subject of multiple complaints by several players, including USWNT star (and former CRS player) Christen Press, in which also involve dismissed complaints that went up to the US Soccer Federation office. We discuss that and how the relationship between the NWSL and US Soccer hierarchy (namely former WNT head coach Jill Ellis) fostered an environment that retaliated against those who supported pro-Black agendas. As the league goes into an offseason of uncertainty, we give our exasperated thoughts on what comes next for the league (also be sure to catch a special Shea Butter FC/Diaspora United 2-part pod that goes into this in much deeper detail). In the 2nd half of the show, Kaiya subs out for Gameday Ty, where we go into the first round of the MLS Playoffs, which saw the Home Team go out in a whimper to NYCFC and our frustration with teams playing in Yankee Stadium, and perennial power Seattle go out in a shock shootout loss to Real Salt Lake, and we give our picks on the 2nd round of the playoffs. Wrapping up the topics we go into the inevitable dismissal of Ole Gunnar Solksjaer at Manchester United following another embarrassing loss, and the potential of Mauricio Pochettino dipping out on PSG to take the United job. In 2UP/2Down we go into car purchases, Thanksgiving greens, and MORE!! To watch this episode and past FTC shows, check out our new YouTube channel, while you're here "Like & Subscribe" and tap that bell so you're notified anytime we add new content! Go to ftcutd.myshopify.com, and get your FTC drip! On Friday 11/26, get your FTCUTD swag with 25% Off with the promo code 25BLACK!! Good thru Saturday!! https://ftcutd.myshopify.com/products/ftc-legends-of-the-culture-series-iii-hoodie Follow us on Social Media! Twitter - @FTCUTD Instagram - @FTCUTD Like us on Facebook - FTCUTD
Good Morning Monaco Tuesday, November 16, 2021 published by NEWS.MC Subscribe to our daily email newsletter Coronavirus infection rate almost doubles Eight Monaco residents tested positive for coronavirus on Monday, November 15. Seven were declared fully-recovered. Orange alert downgraded to yellow Meteo France issued an orange alert for the Alpes-Maritimes and four other Departments at lunchtime on Monday, with high winds and gusts of up to 100 kmh... Asian hornets' nest closes Beausoleil playground The discovery of a nest of Asian hornets next to a children's play area near the Proxi store on ave. Saint-Roman in Beausoleil has resulted in the facility being closed temporarily. Monaco courts Spanish clients HE Ms Catherine Fautrier-Rousseau, Monaco's Ambassador to Spain, and Mr Guy Antognelli, Director of the Tourist and Convention Authority, represented the Principality... Poland to build border wall Poland will build a wall along the border with Belarus starting in December... DULY NOTED: Geraint Thomas, the winner of the 2018 Tour de France, whose bike was stolen from outside a cafe in Menton on Sunday, has had his bike returned. A CRS police unit intercepted a youth riding the machine erratically. Copyright © 2020 NEWS SARL. All rights reserved. North East West South (NEWS) SARL. RCI: 20S08518 - NIS: 6312Z21974 --- Send in a voice message: https://anchor.fm/monacodailynews/message
C'est à la demande du maire que près de 500 hippies ont été délogés par des CRS de leur camp de vacances improvisé. Des blessés et plusieurs arrestations sont à déplorer. Denis Dupont journaliste à L'Indépendant a retrouvé cette archive d'Août 1971 racontant un le lendemain d'une soirée méchoui géante à Villeneuve les Maguelone.
DOWNLOAD SOLCIETY APP NOW! Speaker 1 (00:00:03):Welcome to the Solarpreneur podcast, where we teach you to take your solar business to the next level. My name is Taylor Armstrong and I went from $50 in my bank account and struggling for groceries to closing 150 deals in a year and cracking the code on why sales reps fail. I teach you to avoid the mistakes I made and bringing the top solar dogs, the industry to let you in on the secrets of generating more leads, falling up like a pro and closing more deals. What is a Solarpreneur you might ask a Solarpreneur is a new breed of solar pro that is willing to do whatever it takes to achieve mastery and you are about to become one.Speaker 2 (00:00:41):What's going on Solarpreneurs? We have another fantastic episode and we alive here in Las Vegas, Nevada here in, uh, a man of the hour, his mansion here, just hanging out. So we've got Mr. Jerry Fussell on the show, Jerry. Thanks for coming on with us today.Speaker 3 (00:00:57):Yeah. Thanks for driving up too. I appreciate it. It's how far from San Diego? It's like five hours. Five hours. Yeah. So thanks man, for coming up and hanging out. Glad to have you here at the house. And, uh, thanks for jumping on a podcast with me, man.Speaker 2 (00:01:09):Yeah. I love it. And know Jerry has been treating me to pop tarts and a sandwich. Isn't all, all the pizza I can handle here. So, Hey man,Speaker 3 (00:01:18):It's definitely a house that we house door knockers a lot because pizza and Pop-Tarts and sandwiches that'sSpeaker 2 (00:01:26):Okay. I had more, more food than the first door knocking the house I was in. That's true. All we had was eggs. Pretty much.Speaker 3 (00:01:32):We have a lot of those too. Okay.Speaker 2 (00:01:33):So they got it all, but I know it's been an awesome time here, so yeah, we'd been able to shoot some content and just kind of hang out here with Jerry and his guys. And, um, and the other big announcement we have before we kinda jump into things here is, um, Jerry, he, with his company Pi Syndicate, they are the first ever sponsors of the Solarpreneur podcasts. So, uh we're yeah, I'm happy about it. And we're going to let Jerry talk a little bit about that and then also is partnering on it, but, um, just like the summary of it, they are a, well, I guess you can say, well, it's just a summarized version. Do you want to tell our listeners what pipes in the syndicate is real quick?Speaker 3 (00:02:12):Yeah. Yeah. So Pi Syndicate is more of a supportive kind of mastermind. Um, we didn't start a truly make money. I already have some successful solar companies. My, one of my partners, Mikey, Lucas and Austin already have successful businesses. The reason why we started it is because we realized that about 85% of the guys in the industry that are top earners. So the guy's making, you know, over $150,000 a year, ended up leaving the industry and they have no money. They don't own any real estate. They don't have any money in savings. And about half of them owe money to the IRS. So when we talk about why we work, you know, it's a fun job going door to door, selling stuff. There's a ton of reasons why we all work, but when it comes down to it, if it didn't actually pay us any money, we would all stop.Speaker 3 (00:02:57):And that's eventually what happens is guys get burnt out because the money is not, not good enough to overcome the fact that they owe money on taxes or that they haven't really accumulated any wealth. And it's just, you know, just like you and I, we both probably hopped around to different houses. You know, door-knocking across the country, it's not indicative of saving money. It means that we go buy a BMW when we get enough money or we, we go out to fancy dinners or whatever, we're going to spend the money on. Or we buy our wife a $20,000 wedding ring when we propose because we're making money and guys, uh, leave the industry. Eventually majority of people end up not door knocking forever. Some of us love it. Some of us love it for five years and it's time to move on. And the sad thing for us is when they do move on, they put a lot of sweat and work into the job and they leave the industry with nothing to show for it.Speaker 3 (00:03:47):And these are guys making the top one, 2% of income earners in the entire country, and they're not having any money in savings and investments. And so that's, our mission is to change that we want to, within five years of working in the solar industry, have a plan for retirement in place where a guy can walk away from the door to door, industry, Copia, dentist, whatever he wants to do, and still have a substantial financial portfolio with investing and savings and emergency funds and all the things you need. Also a credit score, enough income to buy your first house. You know, all the things that companies don't really educate their, uh, door knockers on and their sales guys on is really the gap that we fill within the industry. We're kind of selective, but at the end of the day, we want to hang out with cool people that are knocking doors.Speaker 3 (00:04:32):It's just the coolest, single job to meet people that live differently, right. That wake up every day, excited to go to work. Cause if you don't, you quit within three months, probably. So if you're there a couple of years and you're a top earner, you're a guy want to hang out with and be around. And so that's what the mastermind is about is hanging out and being together. The reason I'm so excited to sponsor the podcast is because we feel like you're adding value. Whether it be a new guy that's 30 days in the industry, or maybe just thinking about going into solar, I've heard guys tell me that they've listened to your podcast to make a decision, even to accept a job in the solar industry, which is really cool. But then I would say your normal audience is one of two things, either kind of new to solar.Speaker 3 (00:05:16):And they're looking to see what podcasts are out there. And then the other one, which is strange is like the really seasoned guys like me that just want to hear good conversations with guys that are still in the field door knocking. Part of the reason why I respect you so much is because not only do you do a podcast, but you're still out door knocking virtually every day. So the content is fresh. It's, it's exactly what's going on to help you make money. And when you have guests on the conversations you have with them, um, definitely flow very well because you're doing the same job as them. So it's real life questions. It's real life answers about how to make more money, how to be more consistent in solar. And that's what we really preach is consistency and hard work. And that's the same thing.Speaker 3 (00:05:56):The podcast help brings people that listen to it. So we are super pumped to be a sponsor. And we look forward to being a sponsor for years to come and all the success in the world. We know you're going to hit 500 listeners, um, uh, 500,500,000 listeners. Uh, pretty soon as our goal has a sponsor. So we're going to be boosting some of the marketing and stuff to help you get there because literally everyone in solar right now, everyone in door to door needs to be listening to a mentor, tell them how to do their job better. And we feel like you're a great guy to do that for us.Speaker 2 (00:06:26):I love that. Appreciate that, Jerry. Absolutely man. And yeah, no, it goes without saying too, it's like you were saying so many guys just get out of this and reminds me of the NFL or something. We've all heard like guys in the NFL. I think I heard a stat that like, I don't know some crazy number of them are broke within a couple of years after they can't get out of the NFL. And I feel like door to door is very similar in that guy is making insane amounts of money knocking doors, but let's be honest. We're probably not all going to be doing this stower, you know, retirement age. No. So that's, what's so cool about what you're doing with Pi Syndicate is you're teaching guys how to really hang on to that money and turn that money into future investments in keep a hold of it. Because a lot of people that aren't, you know, super smart with itSpeaker 3 (00:07:08):And, you know, to be clear, um, I wasn't super smart with it either. I started out door to door when I was 19 selling, um, cable, internet door to door and it only paid $30 a sale or something like that. But you could go out and sell 10 of them a day. It's still really good money. And then I became a regional manager and started to make even better money. And, you know, a few hundred thousand dollars was flowing in and I was making all this money. And um, then 26 years old came around. I had my first child and, uh, talking with my wife, I decided to go out and get a real job. I had been in door-to-door for about six years was killing it, making hundreds of thousands dollars a year. I had literally had about a million dollar net worth. And I thought I was doing awesome.Speaker 3 (00:07:51):Right? And then I decided, well, I really want to do something. So I got a job at a children's home. I was working on a college degree and within a year I was completely broke. Um, just completely devastatingly broke, you know, eating ramen noodles again, I'm like, dude, I have a professional college level job. And now me and my wife, uh, are back to eating beans and rice. And we're like, is this what real life is supposed to be? But this is what everyone tells you to go. Do you know what I mean? But what happened is I was living a lifestyle based on being a door to door guy and not everyone stays at door to door guy forever. And so that transition for me was extremely difficult when I realized that I, I thought I want to do something out of it. I thought I wanted a real job, um, that everyone talks about.Speaker 3 (00:08:35):And I'm so glad that I found my way back. And so the first time I engaged with a publisher to write a book, I thought, for sure, my book's title was going to be millionaire by 25 and broke by 26. Um, to really explain why to manage your money better, how to take care of your money. Cause it was a hard life lesson, but it's almost identical to the majority of guys in the door to door industry. And we're not talking about the guy that makes it 30 days and quits. We're talking about guys that are making hundreds of thousands of dollars a year, selling solar pest control roofing. Um, they're not going to last forever. They always think that they want to go do something else. And at, at that point, I don't know of a single another occupation without like being a brain surgeon that you can go and make 300 K a year.Speaker 3 (00:09:20):Like it's just not going to happen. Maybe over 30 years of building it up, even being on wall street, building up, being with a trading company or something like that, you can get there, you know, over years of dedication and working hard with your clients, maybe insurance, you know, there's some things that you can build up this business and make hundreds of thousands dollars, but there's nothing I can think of that you can leave door to door, knowing nothing about anything besides sales and make 300 K year. So there's always going to be this turmoil in your life where you decide to get out of sales. And for me it was, you know, I didn't want to work after five o'clock. I wanted to go home at five, o'clock have dinner with my family. I thought that was the American dream, you know, to have, uh, a normal job.Speaker 3 (00:10:00):I'd get off, go home, eat dinner, have a dog, walk the dog. And uh, I learned very quickly over about a year eating beans that, uh, the American dream wasn't so fun. And I decided to go back to work. But I, at the same time realized there's guys that are not going to decide to go back to work. There's going to be guys that are super happy to make 50 to a hundred thousand dollars a year, but their lifestyle is going to have to change. And just like the NFL players, it was hard for me to adapt my lifestyle to the lower income. So when my wife wanted to go out for anniversary, we still spent $250 on dinner. You know, we still bought, you know, $200 shoes instead of $50 shoes. Like all the things that we had trained ourselves to budget for were all incorrect.Speaker 3 (00:10:43):And we had never had to live on a budget being 21 years old and making 200 grand a year. You don't really have to budget. You just spend your money on whatever you want. And then you're like, oh man, I ran out of money. I need to go knock more doors. And you just can't keep the money coming in. Um, it's not a very smart way longterm to live. So my goal is to get with people that are 18, 19 25, really, you could be 35 and this is the first time you're in door to door. And you're like, this is a lot of money. Those are the guys that we want to help. And they're the same audience that you're trying to help too. So I think there's a lot of alignment there just helping guys get to that next level. So we're excited to help them for that.Speaker 2 (00:11:19):I love that. And yeah, we've had a couple of finance guys and things like that. Come on. But yeah, this is kind of the first, um, you're the first people I've seen really put together kind of mastermind style and help people at this level, which is awesome. So that's why,Speaker 3 (00:11:34):You know, yeah. And the whole thing, the whole thing about Pi Syndicate is it's sharing a lot of the resources for my company, but, you know, we made last year was 151 million. And so the revenue is very large, but then that means I spend hundreds of thousands of dollars a year on legal, on CPAs and advisors. You know, I spent $400,000 last year on mastermind groups. Um, you guys don't have the resource to do that. You're doing really good Taylor, you're killing it. You're in the top of the industry. You're still not going to go out and drop a hundred thousand dollar retainer on an attorney cause you don't need it. Right. It just doesn't make any sense. Your wife would be like, are we getting a divorce? Why do you need the a hundred thousand dollars retainer? Um, so it's just something that you don't think you need until you need it.Speaker 3 (00:12:15):Right? And so it's much better to have my legal team on standby to have our CPAs answer really hard questions to have my tax strategies that you normally only invest in. If you make, you know, $10 million in profit a year or more, uh, be available to you guys. And we do it in a mastermind setting so that we can share the knowledge, um, pretty openly, but with only guys that we want to hang out with, right? There's some guys in masterminds, I'm sure you've been to events and things. You're like, I'd rather not go hang out with a guy afterwards. So we definitely want to make it a group of guys where we stay together for a really long time. And then we want to see your businesses grow, you know? And, um, I would love to see your podcast. I was saying 500,000 listeners earlier.Speaker 3 (00:12:56):I'm not joking about that. I'd love to see your podcast expand to grow. You know, when people talk about the solar guys are listening on podcasts, that should be at my let you know, Jordan Bell Ford and Taylor Armstrong like that. I mean, that's really, when it comes to selling, how many viewers do you need to have listening? And because it's a lot of valuable things, I literally think anyone not listening to your podcast is probably selling the wrong thing. Like they're, they're probably selling cars. They're probably selling watches at a jewelry store, probably selling cell phones. And they're all listening to the wrong podcasts. They think that ed, my let's going to make him rich or grant Cardone and they're not, solar's going to make him rich and they need to be listening to the right box.Speaker 2 (00:13:33):Okay. There's no doubt about that. I mean, I always say we're the Navy seals of the sells industry. No one's selling like we are so we can learn how to sell solar. Then it's like, I mean, that's why we got so much money in this and yeah, yeah. I can translate to anything else to,Speaker 3 (00:13:46):For sure. Yeah. And we definitely have to get good. We got to hone our skills because, um, it's not about how much money even make per job. It's about how much money you make at the end of the year. And we know that this is the gold rush right now. Um, but the guys that made the most money during the gold rush, you know, you've heard the saying that they sold the shovels and they were the support guys. They built the businesses around it. And so yes, we need to be Navy seals. But the reason to hone our skills that much is because it's not going to pay this much forever five years down the road, let's say the average commission is, you know, a thousand dollars a job then instead of 2,500 or more now, um, that's going to be devastating for someone that hasn't hone their skills.Speaker 3 (00:14:26):If they're used to a 5%, 10% close rate and they think they're killing it because they live in California and they're making serious money per sale, uh, that's not going to be around forever. And so the reason why you have to hone your skills is yes, it's nice to make a million dollars a year. This year, selling solar by having a 40% close rate would be awesome. Right? But the real reason is because, um, in five years you're going to have to close at a 40% rate to make the same amount of money you're making today. So if you, this is the training time, view it as a quick start bonus viewed. As you know, the companies are encouraging you to get out there and sell. It's not going to be like this forever. The whole, the law of supply and demand means that the more people that want to sell solar, the less money the companies will pay to sell for us to sell solar.Speaker 3 (00:15:08):Now they're always going to have all commission jobs. So you're always going to be able to make serious money selling solar, you know, look at the other industries, the pest control, the roofing a thousand dollars per sale is still super competitive. And I really believe that's probably where we're going over the next five years. And so we've got to hone those skills because a lot of us that are selling four jobs a month, five jobs a month, a thousand dollars a sell is not going to cut it. We need to be selling, you know, sitting in three appointments a day and selling, you know, one of those a day. Then we start still making good money. Even with the money being turned down, we're still turning out 200,000 a year or more. Um, even when the industry changes, we also need to prep our skills because there's a few times where your skills mean more than just, um, what you can do with them.Speaker 3 (00:15:53):Navy seals end up retiring from the Navy seals. They go into contracting work and there's companies that will pay them millions of dollars to train other people how to do those skills. So when we talk about honing our skills, it's not just about what you can do with the skills, it's about how you can leverage that to help others. And when we, when we talk about even the big guys in sales grant, Cardone never made as much money as he's making until he made a decision to help other people make money. And, uh, same thing with a lot of the other trainers, right? They could go out. There's only so many hours during the day. So, um, they're only gonna make so much money guys like ed, my left that are worth hundreds of millions of dollars, did it by having thousands of people underneath of him selling stuff.Speaker 3 (00:16:35):And that's really what we have to think is I have to get my skills to a level where I can leverage that to help others and in helping others solve the problem, they're going to give me a small amount of a percentage of the problem I solved. So if you help them make a thousand dollars, maybe they're willing to give you a hundred bucks, but while you can only run five appointments a day, guys that are on your teams, running stuff for you could be running hundreds of appointments a day. So it's just the economies to scale are where it's going to be at. So I encourage the guys, listen to this podcast and, um, and really being interested in solar to hone your skills, stop thinking about even your close rate today. Think about what it'll allow you to build in a year and two years and three years, because the economy is not always going to stay the same. So your skills have to up-level. Yeah,Speaker 2 (00:17:20):No, I agree. A hundred percent. And that's why I talk about on the podcast too. I, I encourage all the people listening. I'd go out and teach your teams to sell, develop that skill, to like present to others, to teach other people, you know, they've got all sorts of things. Like you can go to the Toastmasters, the speaking trainings, things like that. I think that's a huge skill to learn because yeah, we're not always going to be, like you said, making as much as we are in solar necessarily right now. So it's important for people that develop those other skills, which are money-making skills, presenting others, training other people, and then you have a whole different set of skill set you can do when maybe solar isn't as good. So, um, yeah, that's huge, Jerry. And, um, we're going to have your partner Austin in, he's going to also talk about pipes and they get to, so we'll leave, um, some, some stuff for him to talk about that too. Um, but yeah, with you, I wanted to hear, I know you talked about a little bit about your background, how you started in selling, but I wanted to hear, how did you transition, uh, specifically into solar sales? And can you talk about how you started your first company with that? And this is obviously super.Speaker 3 (00:18:22):Yeah, so it was a, it was a rough, um, transition. I had, um, gone home and I was selling ADT as a director level. So nice house, no debt. Um, I had everything we needed was making 200,000 a year, thought it was at the top of my game. Um, and then a solar company kept stealing my top reps. So I managed a three or four state region. Um, and they kept stealing reps and it was always my best ones, always the guys that were making 30 deals a month now, all of a sudden our solar reps. So I decided to go to this company because I'm pretty mad. So I'm just going to walk in, I'm a straight forward guy and say, Hey, stop selling my people. I train these people, you know, it's unfair. And the guy said, let me vent for a little while.Speaker 3 (00:19:06):Then he goes, well, don't you ask yourself why they are selling solar? Don't you want to know how much money you could make selling solar. And so I listened to the pitch and I was like, dang, it it's a good pitch. That's way more money than security. Right. And so I was like, okay, I need to take this seriously. So I go home and I talked to my wife and say, Hey, I think we have to make this transition. I had already noticed some of the writing on the wall. ADT had actually not brought on more customers than it canceled since the time that I've been there over the few years that I've been there. And so that was worrying, you know, if we couldn't outsell the cancels, that's a bad thing. And so how ADT dealt with it as they would acquire other companies and kind of fluff their numbers because they're publicly traded.Speaker 3 (00:19:47):So it never looked like they lost subscribers. Um, but it wasn't because of sales. We could not outsell the cancels. Yeah. And so that doesn't sound sustainable to me. So I had already had some fear that no matter how good we sold, it was just a matter of time, five years, 10 years, 20 years down the road that nobody's going to want to buy security door to door for $60 a month payment. Right. So I was just a little bit worried. So I went home and I talked to my wife and we decided to go ahead and me take an offer, you know, and, and go into that. I accepted the offer within the first 30 days. Um, I thought it was going to make all kinds of money and I made one sale. And some, my wife's like, you gotta tell me what's going on here.Speaker 3 (00:20:32):This is crazy. I would also driving three and a half hours to get to the field. So I was at the time because we were trying to save money. I was like, I'm going to do this as cheap as physically possible. I'm going to drive back and forth, you know, as much as I can. And if I have to, I'll just sleep in the car, get up, knock turf in the morning and, and go at it. I had a, a nice SUV. So I lay a whole air mattress. One of those that you see on Amazon where you pump them up, you know, they cover the seats. I was like, this is going to be cool. Yeah. Just hit the doors. It's parked right there. So I was grinding, right. I was not going like 12 hours a day. And uh, my only break for air conditioning was like, maybe go watch a movie or something like that.Speaker 3 (00:21:10):Well, I was like, if you watch a movie, why can't you just go get a hotel? I'm like, well, maybe it's 12 bucks. Like I don't want to stay in a $12 hotel. That's disgusting. And, uh, but it was a grind right. For a whole month and I made one deal and I thought, this is, this has gotta be over. I think our average commission back then was $1,500. So I traded somewhere around $20,000 a month. In that first month I went down to about 1500. And of course you don't get it until they install it. So they gave me like a little bit and they were like, oh, and you'll get the rest just whenever we don't know. And I'm like, oh, I'm in trouble. ADT was like, next day, you know, somebody would be out there installing it. So I misunderstood that coming into solar.Speaker 3 (00:21:48):Where was, where were you selling that? Kansas city. Okay. Yeah, not a great market. It was only about six years ago. Okay. So, and, um, they had a huge rebate in Kansas city and the rebate had gone away the month I started. So we went from having, I think the state level was up to a $2, a watt rebate then had gone down to a dollar watt and then it kind of went away. Well, $2 watt rebate is huge. So our average sell price was like $3 a watt. And, um, between the rebate and the ITC at the time was 30%. We literally were giving away solar for free. So when I accepted the job, I thought I was going to go door to door and just give it away for free. And then like the week I started, they're like, Hey, the rebate's gone away.Speaker 3 (00:22:28):You really guys, it's not free anymore. You need like 25 to $30,000 on every deal. And I'm like, what? I thought we gave stuff away for free. Well, what's going on with this. And so it kind of changed the game really quickly on me. Uh, I adjusted though. So then, um, once I figured out how to sell, I realized that it was a lot about understanding the benefits, understanding the tax taxes, really understanding how much money they would save because I was so new. It allowed me to adjust faster than the guys that have been doing it two years with this huge rebate and everything. And so the next, uh, three months I had made about a hundred sales, I think 102 sales in the next three months. So it really kicked in and I did really, really well. What's strange is you have these self limiting beliefs though.Speaker 3 (00:23:15):I always believed in ADT that I had to sell 30 deals a month and I really peaked out around the same thing. So it's almost like this mindset that I was a 30 deal a month, a rep I carried over into solar as well. And it's just recently that I realized that mindset's completely wrong listening to some of your podcasts with guys. I think you said recently you had someone on that sold 68 deals in a month. So more than double, more than double what I was selling. So I looked back saying, man, I wonder if I totally just carried over a self-belief from selling security that had nothing to do with solar, but I consistently would put up 30 deals a month. The cool thing about solar is there's commercial too. So my last month I killed it. Um, commission wise, I probably would've made somewhere around 280 5k in 30 days.Speaker 3 (00:24:00):So it was incredible. I went home, talked to my wife, we're super excited. We're like, man, this is it. We're making, we love this company. The company's like, Hey, by the way, we can actually afford to pay you that much. And we're nine months behind on install. And I'm like, oh wow, that's crazy. Some of you listening have probably heard words similar to that before, um, from a solar company. So I decided really quickly to go out on my own. Cause I was like, how much worse can it be if they can't pay me? And it takes nine months to install, I'm sure I can do better than that. So, um, the trouble was, I had to walk away from all of that commission and then, um, didn't have a lot of money in the bank. And so cause you know how far behind commissions are.Speaker 3 (00:24:41):So really I walked away from even more than that. And um, but I had no debt on my house and everything. So we had to sell our house. We had to cash out, 401k, invest, everything we had into starting a solar company. And when you tell your wife that it's time to sell the dream house, to go door to door again and sell more solar, it was a hard conversation. I'm so thankful that she supported me through that though and made that leap. Um, it took about three more years of making really minimal amount of money. I think I pulled maybe $30,000 a year out of my company. Okay. The first six months I, uh, you couldn't hire an EPC like you can now they just really didn't exist. Right? And so I had to hire a, uh, NAVSUP trainer to come in and train me to install.Speaker 3 (00:25:25):So the next six months I installed all my own jobs, uh, realized really, really quickly that I was bad at paperwork. So I had to hire administrative shin assistance and people do net metering. And then I realized I didn't like talking on the phone. So I had to hire, uh, an admin person to answer the phone. Then I had to hire, um, um, a phone sales person to answer all the incoming calls. And I'm like, man, this is crazy. Now I have like 14 people that work for me. I gotta, I gotta start making a lot more sales. So, uh, it was kind of the, you know, they say the, the mother of invention is necessity and that was it. I had to learn how to sell a lot more just to support the company, but selling 30 jobs a month, you know, a lot of solar companies don't even do that much.Speaker 3 (00:26:06):So me myself could go out and support my whole company, but then I just kept growing it. You know, when I brought on other sales guys and, but I stay very conservative. So a lot of owners, you know, brag about their, their fancy watches or the drive fancy cars right away. I always knew this was a long-term play for me. And if I was going to expand faster than my competitors, I had to do it, um, through really being wise with my resources. And so I reinvested almost all the money for three years. We lived on about $30,000 a year. Now I had retired from the military. So I lived in California, man. No, no. I lived in Missouri. Yeah. And started the company headquarters. I also had my military retirement. So the medical and I had some pinching coming. So I had more money that, but out of the company, I only pulled the very minimum that my CPA told me.Speaker 3 (00:26:52):I had to pay myself to be legitimate where I wouldn't have probably pay myself anything. And that allowed me to reinvest in marketing and tools and a better management. And you know, it's kind of crazy there for a while that everyone at my company was making more money than me. But at the same time, I knew that long-term, I was gonna make a lot more money than everyone else. So, you know, that's the old saying that you've all heard, but do things that others aren't willing to do. So that later on you can do a lot. And so that's what was able to happen in my life is that there's three years of really investment allowed us to build out a fully integrated solar company. And we were able to get into things that other companies weren't, you know, we go as far as doing the customer's taxes for up to five years after they buy solar, we do internal financing.Speaker 3 (00:27:35):Um, 2020, we did $50 million in internal solar, solar loans, ourselves without paying finance fees. So you just can't do that without a significant amount of resources, but you only have a significant amount of resources when you don't spend resources. And so it was, um, one of those things that we just chose to stay in Missouri, live frugally, know all of our installers. We have a very different, uh, formula to install. They all live out of Missouri and making 2020 $5 an hour in Missouri is incredible. You know, that they can live really well by their home buy nice cars. They live really well. And so they're willing to travel out of Missouri, take the solar panels and go to Minnesota or go to Florida or go to Texas or go to they'll drive all the way here to Vegas to, to install solar panels. Now we try to rack up several jobs in the same week and our teams are really well-trained.Speaker 3 (00:28:25):So a team of three guys can install a job in one day and so they can stack up, um, you know, two teams can travel out here to Vegas knockout, you know, quite a few jobs in 10 jobs in a week and then travel back, you know? And so it's just a different way to look at business. So we try to solve problems, not necessarily spending more money on it, but how do we actually solve the problem? You know, and the most people would say, well, let's just hire a big EPC in Vegas or California or Florida, because that's easier. Cause that also costs a lot of money. And so we make a lot more money in a lot more profit margin because of that. We're also what I would call a white glove service with doing the customer's taxes. So make sure your benefits to the client.Speaker 3 (00:29:07):We are probably one of the more expensive solar companies in the country, um, which is a hard thing, right? Like it's, it's means that some sales reps don't want to work for us because they want to sell for a more competitively priced company. What we do is a process called value stacking, where we believe that once your value stack exceeds the price, that it doesn't matter what the price is, the client will buy it. So we just try to deliver such a tremendous amount of value that we're still able to sell at a higher price. And then we have a very good margin and then we reinvest that margin. And so last year we were able to break $101 million in revenue. I'm extremely profitable. And uh, we owe no money. We have no debt. We have three years of operating capital on hand at all times now.Speaker 3 (00:29:51):So we're the only, debt-free um, three years worth of capital company. I know of specifically in solar, it's nearly unheard of, um, through COVID we had, um, 24 dealerships that were sub-dealers basically under our brand and we were able to support all of them and their reps through COVID. We're able to support all of our staff, even though we shut down operations for install, all the installers cup paid, all the office workers got paid. Wow. And so it's something we're pretty proud of, but it's also means that while other companies buy Ferrari's, I'm still going to be here in 10 years so they can enjoy their Ferrari's and I'll enjoy my, my safety net, uh, money in the bank. It also allows me to have money to help other companies. So I'm an investor in over 50 companies at this point and, um, own equity in those.Speaker 3 (00:30:36):And so, um, those create passive income streams for me, which help, but it's also just a way that I can help other companies because they need the money. And they, unfortunately, most of them weren't good at saving money. They were the guys buying the Bentleys or Ferrari's. And so they come to me and, uh, ended up needing to, to borrow some funds. And I'm happy to do it as long as it's going to help the company and help them longterm. And obviously it helps me if I can own a chunk of their company as well. For sure.Speaker 2 (00:31:01):And now that's one thing I've noticed about you. Jerry is you're very giving gay. I mean, I'm not part of your company or anything, but I come in here, Jerry treats me like family and he's like, dude, all I'll get you a hotel. First thing he says, when I come into their house here, it's like, Hey, I'll get you a hotel room. We don't have like the best beds and stuff here. I'm like down, like, dude, I'll sleep on my couch, no longerSpeaker 3 (00:31:22):Talking about it. And this is a house for doorknockers I ever real bad, but everyone else has twin size bunk beds. And there's a bunch of, bunch of them upstairs, but we were thinking, Hey man, this guy just drove five hours and now he's going to sleep in a bunk bed. We all kind of had this moment where we're like, we probably should have thought this thing through. So we were like, do you want to hotel? Are you cool? And he's like, no, I'm cool. And then right after he said, he's cool. I see one of our guys carrying in a queen size, like Peloton matches. I'm like, thank goodness that somebody went out and bought a bed for this guy. So, um, but yeah. So thanks for saying that, man. I, I believe in this, this theory about investing where, um, if you're investing in the right people, um, there's no bad investment.Speaker 3 (00:32:04):And so even though it may not make monetary sense today or tomorrow, I invest my time, energy and resources and money into people that I want long-term relationships with. Because even though you don't work for me and you may never work with me, or we may never do anything specifically together, maybe you, um, send me a referral and you're like, Hey, am I coming? He doesn't cover Maine because it's the polar opposite side of the country from San Diego. Could you, do you want this referral in Maine? And absolutely I would. And I'll figure out a way to get in and installed a main, even though my install crews, if they're listening right now, we're like, what's Jerry talking about, I don't want to go to Maine. We would figure it out and make money on it. So I just believe in being very giving.Speaker 3 (00:32:44):And I think people will reciprocate that now I'm not stupid about it. I don't give to everybody. I, I give of my time. Um, most sparingly my time is the resource that I can't get back money. I can make more of time. I can't. And so I invest my time into things like the mastermind into my company and to the people I mentioned or indefinitely into things like this podcast, which I think is going to bear fruit for both your podcast and my companies. So by being a sponsor. And so I look forward to, uh, developing our relationship and um, giving him next week, he's going to email me and be like, Hey man, I really need a new Tesla. I was just wondering if he could spot me 120 K cause it's a plan.Speaker 2 (00:33:23):Yeah. I'm not, that'd be the sponsor. Find me a TeslaSpeaker 3 (00:33:28):It's company is going to be like, why is the side of your Tesla say Pi Syndicate on it? That's really weird.Speaker 2 (00:33:35):Yeah. But no, I, I definitely agree with that cause um, I worked with, you know, several different companies at this point too. And um, we were having conversations before this out. You know, some people are more giving stuff than others. And uh, so I think it pays dividends as long as you're smart about it. Like you're saying is just be that guy. That's not like the cheap guy. That's like, oh, this guy is going to nickel and dime me. But if you're investing into relationships, especially, you know, on business level, um, I think it pays dividends. Like I just, matter of fact, last week I did my, a church mission in Columbia down there and that's one of the things and you know, these south American countries, a lot of them are super poor. And so I get hit up all the time about people, ask them for money and stuff like that. So yeah, you gotta get ready, selects selective. But I just sent, you know, 500 bucks last week for a family's funeral that I knew down there and yeah, like, they're like, oh, um, we'll pay you back. We promise, I know 99% chance. They're not going to be, they're not going to pay me back because you know, yeah.Speaker 3 (00:34:31):I've decided, I've decided that, um, I do sometimes give loans, but if, if it's, if you like that, and I think that you're right, you know, there's a good chance. They won't be able to pay you back. I'm very upfront with it and say, it's a gift. And then say, if you're ever at a time in your life where you can give something to somebody else, go ahead and do that because they're going to feel guilty if it's dead, right. They're good people. I'm sure they are. And eventually that's going to wear on them and it's going to impact their life negatively because they're not going to pay you back. Chances are, um, cause they may not have the resources and stuff like that to do that. And so, so think about doing stuff like that as gifts I give my time, lot, I gift things, not connected to any type of repayment.Speaker 3 (00:35:12):Um, and gifting seems to reward me a lot better than loans. So now in businesses, if you want, um, a hundred thousand dollar loan, I'll do that too, but that's a lot, normally stuff like that as somebody in need it, you know, give it as a gift and um, you'll see dividends of that. It also helps you feel a lot better right away. Like it felt good giving them a loan if you had made the decision to just give it to them as a gift, which is basically, it sounds like what you did. But if you had said that in your head, I'm going to give it as a gift and tell them I'm giving it as a gift. It would have had a little bit more positive impact even in your inside yourself. Um, you know, the gratitude that you felt, being able to help someone.Speaker 3 (00:35:48):And so it's a cool way to, to manage your money like that. That the thing that I, uh, one of the things I talk about when I talk about gifting though, is my time. And so I don't know if you've ever heard a term called time vampires, but I, I definitely believe in the concept that there's some people that just siphon away your time. And so while I'm very free to help people and to mentor them and stuff like that, be selective on who you help. Just like you said, you get hit quite a bit for money, the same thing with time. And you're an influential person. You have a lot of value to add to other people's lives, but you have to start being selective. And one of the rules that I've set for myself is that I only interact daily on a day to day basis with 10 people.Speaker 3 (00:36:29):So if I ever get to a point where I'm talking to someone every single day, I either need to figure out if there's somebody I'm mentoring or if they're somebody that needs to be communicating with one of my 10 people. Um, and I have a wife and four kids. So that means I only have five people outside of that to communicate with on a day-to-day basis. So my, my intimate little work circles about five and it makes for some hard decision-making. I talked to the general manager of solar solutions. Um, she's in training for all intensive purposes. She's the CEO. And, uh, I've talked to her one hour in the last week and she's running a multimillion dollar company for me. And I trust that she's doing a great job. Um, but I don't have time. Day-to-day, she's not by any means a time vampire she's listening, but, um, I don't have time.Speaker 3 (00:37:17):So, but making those decisions, even when they're hard decisions like not to talk to your GM every single day, um, mean that it makes it much easier to make a decision about talking to a friend from high school that just wants to chat about video games or fantasy football. Yeah, I cut. I cut them out pretty quickly because if I don't have time for, you know, my GM, I really don't have time for them either. And so setting up some type of structure in your life to make decisions based on time and who you're going to invest time in is very, very important to go a lot further in life if you invest your time correctly.Speaker 2 (00:37:50):Yeah. I agree. That's a good point. So yeah, for all our listeners, I think it's a good thing to do. If another thing I've talked about is just, you know, a time audit, just really tracking what you actually did with your hours, how you spent your time. It's a lot of times we think we're being super productive, smart with our time, and then we actually check it. We just spent two hours talking about fantasy football to someone or, you know, playing a game on the phone, whatever, things like that.Speaker 3 (00:38:15):Yeah. With strangers now that I, uh, last year I had done the math on, you know, how much money I was making per hour that I worked. And the number was much, much larger than what I had previously thought about it being. And, um, in the last few years, it's led me to really, really feel guilty about wasting my time. So like, I, I love video games. I love world of Warcraft back in the day and things like that. There's zero chance that I could open up a computer, get on world of Warcraft tonight and play for four hours without having this tremendous amount of guilt. You know, just because my time is, I know what my time's worth right now. And if someone would ask me, Hey, would you give me $25,000 to play world of Warcraft? I would say, no, I'm not going to give you 25 grand to play a video game. But that's exactly what we do in investing our time and activities that don't actually generate income or generate a better relationship with those around us is it's time that we're really, really stealing from ourselves. Yeah.Speaker 2 (00:39:12):A hundred percent. So now that's a good, a good point with that. And so going back a little bit at Jerry, um, something I wanted to ask you about, we were talking before we started recording here is just like you're saying, um, so many people just sell their prices low. Um, you said you're like one of the higher price companies that sell solar. And I think that's awesome. I started out with the company that was kind of similar to that. They tried to bundle in like some solar cleaning in some like a, I dunno, yearly checkup type things dated. It kind of found some loopholes around it. And I think it made a few customers mad cause they put in the fine print that they would only do that if the customer like contacted them. And It was kind of a, maybe not.Speaker 3 (00:39:54):Yeah. The whole thing about being the most expensive company is you also have to do the best job. And so you can get away with that. What's crazy is it's easier if you're a good salesperson to sell being the most expensive than it is being the cheapest. The only person that thinks it's easier to sell being the cheapest are bad salespeople. That's what it comes down to. You're probably not listening to this podcast. If you think the only way to sell is by lowering the price. That's probably not your target audience. People are trying to learn. They're trying to get better. We grade sales reps, um, AB and C sales reps, um, see sales reps are sell by being cheap. And that's how we remember it. If the only way that they can sell is by being the cheapest in the room and they're not selling based on anything else.Speaker 3 (00:40:39):Then they're a C sells rep. There is definitely room in the solar industry for C sales reps. So if you sell based on price, don't feel bad about it. Just either educate yourself to get better or find a company that really is the cheapest. And that's where you need to, to be out, to make money. Um, be sales reps are those that, um, really are good at one or two things. They either technical experts or they are expert closers. And it's one of two things they're either the best closer in the whole world. I would refer to like, um, Mike O'Donnell or, uh, Taylor McCartney, you know, incredible closers, but I know more about solar than either one of them. So the other, the other B sales rep is, um, someone that, um, is very, very technical. I would look at, um, you know, um, quite a few people in the marketplace that I would look at Jake Hess would be the one that comes to mind, very, very technical, closer, you know, through, um, his academy.Speaker 3 (00:41:34):He trains people how to be very technical. And then the AA sales rep is those that combine both. So yes, Taylor and Mike can definitely answer those technical questions or they know how to pivot really well. And so they're a sales reps because at the end of the day, phenomenal closers and they know everything they need to know about solar to get the sell closed. Now Taylor's kind of bizarre because he does know it just a little bit, but he's that good of a sales rep that he's still in a sales role. And I was talking about something one day. He's like, I don't even know what you're talking about. It's like, okay, I guess I'm more of a technical sales rep instead of as good of a closer isSpeaker 2 (00:42:11):PESI oh, you asked him one time. Like, I don't even know what an inverter is.Speaker 3 (00:42:15):That's what he told me. That's what we were talking about us. I went different numbers, to be honest, I don't know what you're talking about. He's like, but I sold the last 14 doors I knocked on and I was like, wow, that's a that's okay. There's definitely some benefit. I noticed that they and Jake has been hanging out and I'm like, well, uh, hopefully those guys learn a lot from each other because of your powerhouse. Um, but yeah, and so the sales reps are like that. We specifically hire the sales reps because they have to be good closers and they have to know a lot about the technical side. Cause we have to justify our higher price. And um, explain why we're higher. One of the things is we give her a warranties instead of just fake claims. We also give free maintenance, but we give a 25 year true labor warranty.Speaker 3 (00:42:56):Um, anything that goes wrong. A lot of guys in the solar industry don't realize, but they're selling, what's called a workmanship warranty. And under a workmanship warranty, you would assume that if say a panel stops working, that the company would come out and fix it for free without charging the customer a fee, the truth is a workmanship warranty covers bad workmanship. So if they installed it incorrectly, which caused the panel to stop working a good company would come out and fix it. But a good company would do that for free. Even without a warranty in writing, they would say, yeah, you're right. That's our fault. Let us fix that. So it's pretty much just acknowledging that, Hey, we're a good company, which is, which is nice of them to say there's a 20 five-year workmanship warranty, but, uh, under the warranty and most of the terms of that panel stops working.Speaker 3 (00:43:39):It's the manufacturer's fault. You would have to pay that solar company labor to come out and replace that solar panel. And there's almost zero sales reps that understand that concept. And I guarantee you no homeowner understands that concept. So when they get into these 25 year loans, when you talk about company evaluations and how to evaluate the value of a solar company, those that give away a workmanship warranty are basically locking in that customer on a service plan for the next 25 years, that increases the company evaluation because they know they're going to make X amount of money servicing that system over the next 25 years at a company like mine. It actually decreases our company value because we know that the relationship with that client will just cause, um, cost over the next 25 years. So, um, was very few companies like ours that are giving free labor away, true free labor for the whole time, but we definitely do.Speaker 3 (00:44:32):And so we align ourselves up with even our battery manufacturers are full 25 year warranties. So everything we do as a 25 year warranty or more included with labor too. So even the solar panels and the batteries, if we were to go out of business, uh, they'll hire an electrician to come out and service it. So it's just a different pitch, but a good sales rep always feels more comfortable being the guy saying, I'm the best buy for me, then I'm the cheapest, you know, let's, it's a good deal. Let's do this, you know? So you'll kind of weed, weed out those people that aren't quite as.Speaker 2 (00:45:03):Yeah, I know. Yeah. It's interesting. If you go to these like marketing conferences and stuff, and then the online marketing and they say, there's no competitive advantage to being like, you know, unless I made all of the pack pricing, you're either like the cheapest or you're in the most expensive and you add more value, but there's no like advantage at all as being kind of like middle soSpeaker 3 (00:45:23):No, and you kind of disregard all the middle companies too. Um, and so I, I definitely think one of our strategies is we know we're going to be the most expensive. So we get that out of the way right away. We tell them we are, we actually tell them to shop around. And if they choose to go with a cheaper company, we'll even pay $50 per quote, that they give us from the other companies that they've shopped around with. So we encourage them to give us, go shop around with four quotes and then we'll come back and be the final one in the door, propose our price a hundred percent of the time. They're expecting us to undercut the cheapest bid. Um, cause they think it's a gimmick, right? You're giving me these quotes, you're going to undercut their price and then try to close me a hundred percent of the time.Speaker 3 (00:46:01):We make sure we're more expensive. In fact, if we're not the most expensive person, we raise our price by a thousand dollars and make sure because it's easier to sell in the most expensive. Now, not everyone buys though. And so just like a car lot, you you're the most expensive your Lamborghini dealership or whatever. That's how we treat it. But at the end of the day, if you say it's too expensive and you're getting ready to walk out, we say, hold on, wait a minute. Let's see if we can throw something else in. So we try to do value, add. So we may replace their air conditioner or we may help replace the roof or whatever it is. But very rarely will we do just a straightforward discount. We're never going to be like, okay, you're right. Let us let us price it out for $10,000 cheaper. There's probably not going to be us, but we'll win.Speaker 2 (00:46:42):Yeah. I think that's awesome. Because especially in California, there's no excuse for people to be selling like rock bottom prices. I mean, San Diego, you can sell a system, you know, $6 a watt, super expensive, and you're still saving them. You're still cutting their bill by 30%. Yeah. So it's like these companies that try to sell rock bottom line, what are you guys doing? We're still saving the customers.Speaker 3 (00:47:03):I think we all need to be on the same team, right? Like, um, I think there's places out there for the cheapest guys. The problem is, um, those guys need to go move to Missouri or Kansas or somewhere with 10 cent per watt, kilowatt hours of they want to sell cheap California. You're not competing against each other. You're competing against a utility company. So $6 a watt is completely fair price to charge. If you're versing the utility company, what that allows you to do as a company is make more profit. There is absolutely nothing wrong with profit. If you're helping the client, because that means you can take that profit and go make more clients. You can spend more money on marketing. You can spend more money on paying your people. You can spend more money on office space. You can do everything you can to grow.Speaker 3 (00:47:47):And at the end of the day, we all want to have more solar customers. We all believe the solar is good for the environment. And so at the end of the day, our mission is to sell as many people as we can. And people get twisted. People that are new to business think selling cheaper will help them sell more. It absolutely will. Not their resources you gain from selling a fairly priced product. That's beating out your competitor, which is the utility company is the correct price. And so I would never charge somebody. One of my ethical roles is I never charge more than what they're paying on the utility company. So solar solutions is a little different. They have to be able to pay the system off within 10 years through savings. And they have to be able to have a payment that's cheaper than their utility bill from day one, or we won't quote them.Speaker 3 (00:48:30):The system will tell them that they w we don't advise them to go solar in California. That wouldn't happen very often though. It's so good of a deal for everybody. Even as $6 a watt, you should be doing that, just make sure you're not going out and buying Ferrari's. You need to be reinvesting that money in yourself. And for you specifically in your podcast and your recruiting budget to help others come on board, because you're not going to be able to sell a prices like that forever. And we know that. So you use those resources to expand, to grow, to really make a dent in the industry. And it's so cool. I, I learned something from you earlier. We were talking to our guys about how saturated Las Vegas is. I don't think anyone would argue that San Diego's, if not the most saturated market, one of the most saturated markets in the United States, very cool market.Speaker 3 (00:49:17):And you still go out and door knock every day, and you still run into people that need solar and once solar. So it's incredible. We, we need to stop thinking of the scarcity mindset, where we're competing against other solar companies. We're still not even in San Diego. We're not. Um, and the truth is you mentioned it too, but those companies may knock the door once and you're going to knock the door five or more times. And so, um, I'm okay with competition as long as I'm better than them. And it sounds like you're, you're beating them so that that's healthy competition. Um, and so I think that that's a really cool thing to think about. We all need to keep our prices higher because in San Diego, if you can sell $6 a watt in the most competitive thing in the whole United States, that everybody should be pricing their structure out right below the utility company, let's do better than the utility company. But that means I operate in mainly the Midwest states. That means we don't sell as high in Kansas. We don't sell high in Texas. We don't sell as high at all in Tennessee. So it, it just all depends on where you're at, what their pricing is because the utility is the competitor, not, not the other solar companies. Yeah.Speaker 2 (00:50:21):I think that's a good rule to go by though, cause you don't want to charge them way more than they're paying forSpeaker 3 (00:50:26):Electricity. Heard some interesting guys pitch it. And if they knocked on my door, their ride, I probably would've bought it cause they're good enough to pitch, pitch it as an investment. Um, my individual role with investing is I want my money back within 10 years. I want it to completely be liquid. And, and that's really comes into about a 7% compounded interest rate or above. And so, um, I wouldn't personally make an investment that, that wasn't going to happen. I put all my money into investments like that. So why would solar be anything different if I'm going to put it on my house? I still want that kind of ROI. And so, um, I think I just ethically on a personal side, uh, that's translated to the ethics of my company to say, look, we're not going to sell it unless, unless they meet the standard for Jerry thinking, it's a good thing.Speaker 3 (00:51:13):Right? And that's my standard. There's, there's been some guys though that I talked to that view it as a financial investment in states that have very low prices and I don't think they're wrong. And there's also a lot of speculation about the price of utilities, really jumping up over the next three years. A good friend of mine, Mike [inaudible] talks about it. He's extremely convincing, right? Like he's the guy that I've listened to enough where I'm like, you know what, even if they are spending $20 more a month, Mike's probably right. It's, it's going to be okay. It's just not a company thing that we do. So that's our litmus test is we try to price it right below. Um, but definitelySpeaker 2 (00:51:48):Don't price it a dollar 85 watt. I think we can all agree that if you're the guy out there selling at a dollar 85, a watt, you need to listen to the podcast more often and learn how to sell more because there's no reason to do that. And at the end of the day, what I tell customers that are getting an incredible deal as I run the numbers and I say, Hey, your sales reps making $500 on this deal. Uh, who is it? Oh, it a power I've never heard of power. That's interesting. It must be a power app. Um, the sold out for a $500 commission. And I say, think about this, it's a 25 year agreement. Uh, you, you need customer service for the next 25 years. If something goes wrong, right. They're like, yeah, nice. Well, how much do you think the $21 a year is going to buy you in time for that guy to pick up the phone and answer your questions?Speaker 2 (00:52:33):The truth is, think of his commission, like prepaying to have an advocate for you for the next 25 years. And in my opinion, $500 is not enough money for a 25 year relationship. So we need to pay our reps well enough that they're do very good customer service or the company needs to make enough profit that they take that role on themselves. That the rep isn't the one responsible for customer service and taking care of. Cause if we sell somebody a $25,000 system, it is definitely our responsibility to take care of them for the next 25 years. Like that's, that's just the way it is. That's our job. Yeah. So yeah, I just got a call actually like a couple hours ago from Gaia sold four years ago. Call me just barely ins. Yeah. Luckily I made more than 500 bucks, but yeah, that's a good point though. Like I'm only making 500 bucks and it's a guy that's taken up all this time. That's time suck then. Uh, yeah. It's um, like you want to be making, you know, your time worth some money for sure. Yeah. Um, and yeah, the other thing that's, uh, I forget, I forget the question. I was going to ask you where I was going with.Speaker 3 (00:53:41):Well, we were talking a little bit, uh, before we started and you were, you were basically saying, um, you know, why did I step away from solar solutions? And, um, you know, I thought that was a really interesting question that I wanted to say for the podcast. Yeah. So the reason why is because I, I believe that the solar industry is at its peak right now. I think it's incredible. It's the new gold rush. Everyone we know in sales should be going into solar right now. It is the biggest opportunity. If you're not telling your friends and family members and neighbors, neighbors, that they should be selling solar, and they're working at a library or they're working at Starbucks, you're doing them a disservice. You should be so convicted that it's time to get into solar, that I needed to transition what I'm doing to align with that.Speaker 3 (00:54:26):So if I believe everybody should get into solar, that I need to build a company that isn't one of the most difficult sales processes that requires a rep like you with all your knowledge, to go out and sell for $6 a watt, I would need to do something more moderate. So energy co is meant to recruit anybody. You know, we're here at a recruiting class. I'm glad that you're able to say Hey to them while you were here. And there's some kids are now in this class that are 18 years old. There's not a lot of solar companies. I'd be excited about hiring a 18 year old. Right. And I had to go back to a training model that allowed me to recruit literally anybody off the street. Like I worked in a Starbucks that teacher, the person that's struggling. Cause they got a degree in psychology and they haven't worked since they graduated.Speaker 3 (00:55:12):They're like, what just happened? I paid all this money for a degree and I don't have a job. I wanted to go back to the days, like when we worked at security or pest control that literally anybody could do it. Right? Like you just had to knock doors. Solar gets more complicated than that sometimes. And so our whole concept here at energy co is a division of labor. So we split it into the, the setter, the educator and the closer they work together as a team, you know, there's a whole bunch of people that can set cause anybody can set just like in pest control security. He just got to say, even if they're terrible and they're like, Hey, do you want solar? Eventually somebody's going to say yes. Whereas the educator's a little bit harder. You've got to explain the one-on-ones and how solar works.Speaker 3 (00:55:51):But there are a whole bunch of second grade teachers out there that would absolutely love to make money per job. Um, in 30 minutes of work, right? And then our closers are definitely the rarest people. It takes a very specific skillset. And so w
In this special sponsored episode of the Auto Remarketing Podcast, Doug Hadden of ACV is back on the show to talk about the company's Single Inspection App, its participation and presence at the upcoming Used Car Week event and much more. Hadden is among dozens of speakers, including several from ACV, set to take the stage at Used Car Week, Nov. 15-18 at Red Rock in Las Vegas. He is leading a Pre-Owned Con workshop sharing how to "Work Smarter Not Harder: Machine Learning & AI Lead to A+ CRs."
An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center and Dr. Monalisa Ghosh from the University of Michigan Health System, authors on “Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.” They discuss recommendations for management of irAEs in patients treated with CAR T-Cell Therapy in Part 2 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] 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 we're continuing our series on the management of immune-related adverse events. ASCO has developed two guidelines for the management of immune-related adverse events-- one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy. In our last episode, you heard an overview of the Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Today, we'll be focusing on the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline, and we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy. Today, I am joined by Dr. Monalisa Ghosh, from the University of Michigan Health System in Ann Arbor, Michigan and Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, authors on both Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline and Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Thank you both for being here, Dr. Ghosh and Dr. Santomasso. In addition, 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 full Conflict of Interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Ghosh, do you have any relevant disclosures that are directly related to this guideline? MONALISA GHOSH: No. I do not have any relevant disclosures. BRITTANY HARVEY: Thank you. And, Dr. Santomasso, do you have any relevant disclosures that are directly related to this guideline? BIANCA SANTOMASSO: Yes. I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of CAR T-cell therapy side effects. BRITTANY HARVEY: Thank you. Then, getting into these immune-related adverse events-- first, Dr. Ghosh, can you give us an overview of the scope and purpose of this guideline? MONALISA GHOSH: Sure. The purpose of this guideline is to offer expert guidance and recommendations on the management of immune-related adverse events in patients treated with chimeric antigen receptor or CAR T-cell therapy. This guideline offers guidance on the diagnosis, evaluation, and management of the most common toxicities of CAR T-cell therapy, which includes Cytokine Release Syndrome-- or CRS-- and immune effector associated neurologic syndrome-- or ICANS. As well as other potential, but less common toxicities, such as Hemophagocytic Lymphohistiocytosis-- or HLH-- B-cell aplasia, prolonged and recurrent cytopenias, Disseminated Intravascular Coagulation-- or DIC-- and infections. BRITTANY HARVEY: Great. Thank you. Then, Dr. Santomasso-- looking at this guideline, there's a few overarching recommendations. So, what are those general recommendations for the management of immune-related adverse events in patients receiving CAR T-cell therapy? BIANCA SANTOMASSO: Yes. The overarching recommendations are, really, first to recognize that these side effects exist. And that, as such, it's important to recognize that patients who develop these toxicities or side effects after CAR T-cell therapy need to be evaluated, or managed in, or transferred to a specialty center that has experience with the management of these toxicities. They're new toxicities. This is a new therapy. And patients are increasingly going to be managed in, or treated in, the outpatient setting, and, as such, they need to remain within a short distance of the treating center for about four to eight weeks post-therapy, and they should then return to their treating center upon experiencing any toxicities. Finally, as its flu season and infection season, it is recommended that inactivated influenza and COVID-19 vaccination be performed on patients and also family members as well. And any patient who does have an active infection, the CAR T-cell infusion should be delayed until that infection has been successfully treated or controlled. I often make a final point, which is that the immunogenicity of and efficacy of COVID-19 vaccines is uncertain in these patients with these agents, but the potential benefits outweigh the risks and uncertainties for most patients. BRITTANY HARVEY: Thank you. Those are important points for patients and treating clinicians. So then, Dr. Ghosh-- as you mentioned, this guideline addresses the seven most common CAR-T-related toxicities, and I'd like to review the key recommendations for each of those. So let's start with, what are the key recommendations for identification, evaluation, and management of cytokine-release syndrome? MONALISA GHOSH: Well, Cytokine Release Syndrome is one of the two major toxicities that occur immediately or within a short time period after infusion of CAR T-cells. We have defined Cytokine Release Syndrome, or CRS, as an immune-mediated phenomenon that's characterized by various symptoms that are indicative of immune activation and inflammation. And patients may experience signs and symptoms that could include fever, hypotension, hypoxia, tachycardia, shortness of breath, rash, nausea, headache, and various other symptoms that are a little less common. These symptoms are caused primarily by the release of cytokines. Cytokines are the messengers of the immune system, and most of them are released by bystander immune and non-immune cells. We know that the onset of Cytokine Release Syndrome is variable depending on the CAR T-cell product that's used, as well as the patient population that's treated. But it generally occurs anywhere from two to seven days after infusion of CAR T-cells, and in some rare cases can occur even a little bit later. A standard grading system has been developed and grade CRS, or Cytokine Release Syndrome, based on three parameters-- fever, hypotension, or low blood pressure; and hypoxia or low oxygen levels. CRS is primarily managed with IL-6 antagonists because IL-6 is an inflammatory cytokine that has been shown to mediate a lot of the systemic effects that we see from Cytokine Release Syndrome. And one of the treatments is the monoclonal antibody tocilizumab, which acts against-- or blocks-- the IL-6 receptor. CRS that is refractory to tocilizumab is generally treated with steroids. Then there's limited experience with additional therapies, especially in the setting of CRS, that does not respond to tocilizumab or steroids. There are other anti IL-6 therapies available. For example, siltuximab, which binds to IL-6 itself rather than the IL-6 receptor. However, there have been no direct comparative studies of these agents. Anakinra, which is also an IL-1 receptor antagonist has also been shown to mitigate CRS in some CAR T-cell recipients that have high grade CRS. BRITTANY HARVEY: OK. Thank you for reviewing those management strategies. So, following that-- Dr. Santomasso, what are key recommendations for identification, evaluation, and management of immune effector cell-associated neurotoxicity syndrome? BIANCA SANTOMASSO: Sure. Immune Effector Cell-associated Neurotoxicity Syndrome-- also known as ICANS-- is the second most frequent severe toxicity that can be seen after CAR T-cell therapy. So, what is ICANS? These are transient neurological symptoms that occur in the days after infusion, most commonly with CD19 CAR T-cell therapy. And the clinical manifestations of ICANS include encephalopathy, which is confusion, behavioral changes, expressive aphasia, or other language disturbance, change in handwriting or other fine motor impairment or weakness, and tremor and headache can also be seen. In more severe cases, patients can become obtunded with a depressed level of consciousness or even develop seizures, and they may require a higher level of ICU care, such as intubation for airway protection. And in very rare cases, malignant cerebral edema may develop, which may be fatal. ICANS can occur at the same time as Cytokine Release Syndrome, or can also occur several days after or shortly after CRS resolves, so it's important to have a high index of suspicion even after Cytokine Release Syndrome has resolved, but typically the side effects are self-limited and occur within the one month after infusion. Most symptoms lasts between 5 and 17 days, and the time of onset duration and severity of ICANS may really vary depending on the CAR T-cell product used or the disease state of the patient. So, what do I mean by that? Patients with high disease burden seem to be at increased risk for severe ICANS, so kind of knowing the disease that the patient has and the burden of disease is important. And then also there may be product-specific differences as well, so reviewing the product label is important as well because each may have its own risk evaluation and mitigation strategies that inform both the duration and the frequency of monitoring for ICANS after infusion. For evaluation of ICANS, we recommend, again, the ASTCT ICANS grading system. These allow for monitoring of several different aspects of neurologic function in these patients. Mental status changes are really what define the onset of ICANS. So for CRS, it's fever; for ICANS, it's mental status changes. And the severity of the mental status change can be determined by a standardized score known as the ICE score, which stands for Immune Effector Cell-associated Encephalopathy score. This is a simple 10-point scoring metric where points are assigned for orientation to year, month, city, hospital, ability to name three objects, ability to follow simple commands, write a standard sentence, and count backwards from 100 by tens. And for children younger than age 12 or those with developmental delay, The Cornell Assessment of Pediatric Delirium, also known as the CAPD, can be used in placement of the ICE assessment. Prior to CAR infusion, patients should be evaluated, including with an ICE score, for their baseline neurologic status. And what's nice is that this ICE assessment can be used as a daily screen after CAR infusion for the onset of ICANS during at-risk period. Then, other than the ICE score, there are four other neurologic domains that contribute to ICANS grading, and that's level of consciousness, seizures, severe motor weakness, and signs and symptoms of elevated intracranial pressure or cerebral edema, and patients are graded according to the most severe symptom in any of the five domains. So for patients who develop ICANS, it's recommended that they have workup, including blood work, CRP, CBC, comprehensive metabolic panel, fibrinogen, and coagulation tests. Neuroimaging with a non-contrast CT of the brain should be done and considering MRI of the brain in patients who are stable enough. In addition, electroencephalogram and lumbar puncture should be considered. And the electroencephalogram is really to rule out subclinical seizures, and the lumbar puncture is to assess the opening pressure-- or the pressure within the central nervous system-- and also to send studies to rule out infection. And again, these all have to be considered on an individual case by case basis, but are things to keep in mind. So for treatment of ICANS, the mainstay of treatment is, really, supportive care and corticosteroids. Tocilizumab, while it seems to rapidly resolve Cytokine Release Syndrome and most symptoms, actually does not resolve ICANS and may worsen it, so steroids are really typically used. The typical steroid is dexamethasone at a dose of 10 milligrams, and the interval really depends on the grade of the ICANS. Because of the possibility that tocilizumab may worsen neurotoxicity, ICANS really takes precedence over low grade CRS when the two occur simultaneously. And patients who don't show improvement within 24 hours after starting steroids or other supportive measures should have CSF evaluation and neuroimaging. Often treatment of seizures-- many patients are put on Keppra and levetiracetam or other anti-seizure medicine if they develop ICANS, and patients with grade 3 or greater ICANS may need an ICU level of care and escalation of steroid doses. The steroids are continued until ICANS improves to grade 1 and then tapered as clinically appropriate. And the most important thing to remember is that ICANS just needs to be monitored very closely as patients may worsen as some steroids are tapered. They also may improve rapidly after steroids are started, so steroids should be tapered quickly as patients improve. And, again, as with CRS, there's limited experience with other agents, such as Anakinra and siltuximab, but those could be considered in severe or refractory cases. BRITTANY HARVEY: Understood. I appreciate you going through when and how clinicians should screen for ICANS and those key management points. So, in addition to that-- Dr. Ghosh, what are the key recommendations regarding cytopenias? MONALISA GHOSH: So cytopenias can occur post-CAR T-cell infusion, and they can occur either in the early phase or in the later phase after CAR T-cell infusion. Meaning that they can occur early within the first few days to weeks post-CAR T-cell therapy or could even occur months to years later. These cytopenias include anemia, thrombocytopenia, leukopenia, neutropenia. Many patients may present with fatigue, weakness, shortness of breath, lightheadedness, frequent infections, fevers, bruising, and bleeding, and the symptoms usually are consistent with how they would present otherwise with anemia, thrombocytopenia, or neutropenia. Acute cytopenias within three months of CAR T-cell therapy are more common. This is due to usually the lymphodepleting chemotherapy that is administered prior to CAR T-cell therapy. Most patients receive a combination of fludarabine and cyclophosphamide prior to CAR T-cell infusion, or they may receive another agent, such as bendamustine. Most patients also come into CAR T-cell therapy with low lymphocyte counts from previous therapies. Early cytopenias, as I mentioned, are generally due to lymphodepleting chemotherapy or other recent therapies. There also could be an immune-mediated process due to the CAR T-cells. Usually prolonged cytopenias which occur beyond three months post-CAR T-cell infusion can be seen in a small number of patients. And the mechanism of prolonged cytopenias is really unclear at this time, but likely multifactorial. Most recipients of CAR T-cells who have prolonged cytopenias beyond three months post-CAR T-cell infusion should have a standard workup to rule out other common causes, such as vitamin or nutritional deficiencies. They should also have testing such as bone marrow biopsy and scans to rule out relapse disease-- relapse lymphoma or leukemia, for instance, that could be causing these cytopenias. Other examples would be myelodysplastic syndrome or other bone marrow failure syndromes. So cytopenias are generally managed with supportive care including growth factor and transfusion support. This applies to both cytopenias in the early period post-CAR T-cell therapy or more delayed prolonged cytopenias. In patients who have prolonged cytopenias of unclear cause that could be immune-mediated, other interventions such as high dose IVIG or even steroids could be considered depending on the situation. For those that have cytopenias in the first few months post-CAR T-cell therapy, generally they are monitored and treated with supportive care, and these cytopenias eventually resolve in the majority of patients. BRITTANY HARVEY: Great. Those are important considerations. Then, Dr. Santomasso, what are the key recommendations regarding Hemophagocytic Lymphohistiocytosis? BIANCA SANTOMASSO: The major recommendations for the identification, evaluation, and management of Hemophagocytic Lymphohistiocytosis, or HLH-- this is also known as macrophage activation syndrome. First, let's just start by saying that this is a dysfunctional immune response, and it's basically characterized by macrophages which are revved up and hyperactive and also possibly lymphocytes as well. There are high levels of pro-inflammatory cytokines during this state and tissue infiltration, and hemophagocytosis, and organ damage. This can occur outside of the context of CAR T-cell therapy, either as a primary HLH or secondary HLH that can be either triggered by infections, or autoimmune disease, or cancer-- especially hematological malignancies, but HLH has also been observed as a rare complication of CAR T-cell therapy. And outside of the setting of CAR T-cell therapy, HLH is defined by fever, cytopenias, hyperferritinemia-- or high ferritin level-- as well as bone marrow hemophagocytosis. And what's interesting is that this is very similar to what's seen during Cytokine Release Syndrome, and that can make it difficult for patients who have moderate to severe CRS to distinguish that from HLH. The laboratory results may be very similar. So the key to recognizing HLH is really to have it on your differential even though it occurs rarely after CAR T-cell therapy. It may occur with slightly different timing and may require more aggressive treatment. The lab alterations can include, again, as I mentioned, these elevated levels of several cytokines, such as interferon gamma. We can't normally send those in the hospital or the clinic, but sometimes soluble IL-2 receptor alpha can be sent and serum ferritin can be sent, and that's an especially useful marker. There have been diagnostic criteria for CAR T-cell-induced HLH that have been proposed, and these conclude very high ferritin levels-- over 10,000-- and at least two organ toxicities that are at least grade 3, such as transaminitis, increased bilirubin, renal insufficiency or oliguria, or a pulmonary edema, or evidence of hemophagocytosis in bone marrow or organs. Unlike other forms of HLH that occur outside of the context of CAR T-cell therapy, the patients may not have hepatosplenomegaly, lymphadenopathy, or overt evidence of hemophagocytosis. So just because a patient may not show those yet doesn't mean that HLH shouldn't be considered. If we see patients that have a persistent fever without an identified infection source or worsening fever, we basically should be considering HLH and doing the appropriate workup and treatment. Patients with HLH often have low fibrinogen, high triglycerides, and also cytopenias as well. The treatment-- just as there's an overlap kind of in the signs and symptoms, the treatment and the clinical management overlaps as well with CRS, so tocilizumab is typically administered. But corticosteroids should really be added for these patients, especially if there's clinical worsening or grade 3 or greater organ toxicity. And if there's insufficient response after 48 hours of corticosteroid therapy plus tocilizumab, many centers consider adding another medication such as Anakinra. I'll finally make a comment that, outside of the context of CAR T-cell therapy, HLH is sometimes treated with cytotoxic chemotherapy, such as etoposide. This approach generally is not used as a first line for patients undergoing CAR T-cell therapy due to etopiside's documented toxicity to T lymphocytes. And generally, the corticosteroids, plus the anti IL-6 agent, plus Anakinra is considered the first line of management. BRITTANY HARVEY: Got it. That's an important note on the management of HLH, and a great note on distinguishing CRS and HLH. So in addition, Dr. Ghosh-- what are the recommendations for management of B-cell aplasia? MONALISA GHOSH: B-cell aplasia, it's a disorder that's caused by low numbers or absent B-cells. And this is particularly relevant to CD19 directed CAR T-cell therapy, which is what most of the CAR T-cell therapies that are available right now target. They target CD19, and CD19 is present on normal as well as malignant B-cells. So most patients who receive anti-CD19 CAR T-cell therapy will develop B-cell aplasia at some point, and B-cell aplasia may be temporary or prolonged. It usually does, on one hand, indicate ongoing activity of the CD19 CAR T-cells and can be used as a surrogate marker. And increase in CD19 CAR T-cells could, in some patients, signal impending relapse, or dysfunction, or absence of activity of CD19 CAR T-cells. B-cell aplasia in CAR T-cell recipients is really due to, as I mentioned, an on-target, off-tumor effect. It can be prolonged and there is variability in rates of prolonged B-cell aplasia. The most significant consequence of B-cell aplasia is that it can lead to low immunoglobulin production. And immunoglobulin production is a very important part of the immune response by providing antibody-mediated immunity, so patients may present with frequent infections and low immunoglobulin levels. For most CAR T-cell recipients, this can be managed with infusions of Intravenous Immunoglobulins-- IVIG. However, the presence of B-cell aplasia can also present other challenges-- especially during this current pandemic, as Dr. Santomasso alluded to earlier, that it is unclear if patients will be able to mount a sufficient enough antibody response to the COVID-19 vaccines available since they cannot produce significant amounts of antibodies. This is an active area of research. However, we do advise that all CAR T-cell recipients do get the COVID vaccine and also other seasonal vaccines, such as the influenza vaccine. So it remains to be seen. We need some more long-term follow-up studies on how many people who receive CD19-directed CAR T-cell therapy will have prolonged B-cell aplasia and what the consequences will be. At this time, it is suggested that patients have their IgG levels monitored and-- if possible-- their actual B-cell numbers monitored. And if their IgG levels drop below a certain number, then they may receive IVIG infusions intermittently. We recommend in this guideline using 400 as a possible cutoff for IgG levels prior to administering IVIG. However, if patients have higher IgG levels and they have recurrent or life threatening infections, infusion of IVIG is recommended as a consideration to help boost the antibody response. BRITTANY HARVEY: OK. As you mentioned, those challenges are particularly relevant now. So then, Dr. Santomasso, what are the key recommendations regarding Disseminated Intravascular Coagulation? BIANCA SANTOMASSO: Disseminated Intravascular Coagulation is a disorder that's characterized by systemic pathological activation of blood clotting mechanisms, which results in both clot formation throughout the body and also bleeding. There's an increased risk of hemorrhage as the body is depleted of platelets and other coagulation factors. So it's basically important for clinicians to be aware that DIC-- or Disseminated Intravascular Coagulation-- can occur after CAR T-cell therapy, and it can occur either with or without concurrent Cytokine Release Syndrome. The treatment is primarily supportive care and replacing the factors, such as fibrinogen-- based on the levels-- and also replacing factors based on partial thromboplastin time and bleeding occurrences. But corticosteroids and IL-6 antagonist therapy can be used if there is concurrent CRS or in the setting of severe bleeding complications. There is limited evidence for other interventions. BRITTANY HARVEY: Great. Appreciate you reviewing those. So then, the last category of toxicity addressed in this guideline-- Dr. Ghosh, what are the key recommendations for identification, evaluation, and management of infections? MONALISA GHOSH: So a variety of infections can be seen after CAR T-cell therapy. And there are many factors that can lead to infection after CAR T-cell therapy including the presence of cytokines, such as neutropenia or leukopenia and B-cell aplasia that we earlier discussed-- leading to low immunoglobulin production and protection. As well as the increased risk of infection due to use of high-dose steroids to treat CAR T-cell-related toxicities, such as ICANS or CRS. Early after the infusion of CAR T-cell therapy-- that is, within three months-- patients often develop neutropenia due to lymphodepleting chemotherapy and/or the CAR T-cells themselves. And these patients are particularly susceptible to infection, so most of the infections that occur early on tend to be bacterial infections, and a few fungal infections have been observed as well. Patients who receive high-dose steroids for high grade CRS or ICANS have been shown to have increased serious infectious complications including bacterial infections, fungal infections, as well as viral reactivations. Infectious complications that occur later are often due to hypogammaglobulinemia due to B-cell aplasia and reduced production of immunoglobulins. And treatment is typically directed at the infectious source, as it would be even if these patients did not have CAR T-cell therapy. There are some prophylactic antimicrobials that are recommended for CAR T-cell recipients who have prolonged cytopenias. Especially those with prolonged neutropenia should be on some sort of bacterial and/or fungal prophylactic antimicrobials. Patients should also be monitored for hypogammaglobulinemia long term and should receive intravenous immunoglobulins as needed. As we have mentioned a couple of times already, being very aware that these patients are also more susceptible to seasonal infection, such as influenza, is important, and so vaccinations are very important for this patient population. Vaccinating against influenza and vaccinating against COVID-19. BRITTANY HARVEY: Thank you both for reviewing those key points for the most common CAR T-related toxicities. So, just to wrap us up-- Dr. Santomasso-- in your view, how will this guideline impact both clinicians and patients? BIANCA SANTOMASSO: Well, I think we've seen now that cell therapy is really one of the major advances in cancer treatment in the past decade. And I think it's reasonable to expect more of these cell therapies to be developed, and we'll hopefully see their use extend beyond very specialized centers. But CAR T-cell therapy side effects are manageable if they're recognized, so I think this guideline helps that, and they're reversible with proper supportive care. They can be serious and they require close vigilance and prompt treatment. But, again, we believe this guideline and recommendations will help members of clinical teams with both the recognition and management of all of these toxicities, and that will help patients by increasing their safety. BRITTANY HARVEY: Great. That's important to note that these toxicities can be severe, but are also manageable. So I want to thank you both for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso and Dr. Ghosh. BIANCA SANTOMASSO: Our pleasure. MONALISA GHOSH: Absolutely. It was my pleasure. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events in patients treated with immune checkpoint inhibitors. To read the full guidelines, go to www.asco.org/supportive care guidelines. 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. [MUSIC PLAYING]
The job of an MLS/Association is never over! Mike Sandoval, professional development manager at the Huntsville Area Association of REALTORS®, sits down with CRS Data's Nikki Morgan to discuss all the ways an association can make a difference for its members. Together, they explore the impact of hybrid training options and how the team helps members leverage data and mapping tools. He delves into the MLS Tax Suite's new School Zones tools and various other features. He explains the ins and outs of how his membership is using new enhancements tools, including Spanish reporting options and ADA functionality, to service clients more successfully. Mike has a heart for helping new professionals expedite the learning process and for veterans, he offers a wealth of new ideas and perspectives. Whether it's prospecting, sales, training or marketing, he breaks down his powerful, accessible ideas flawlessly. Enjoy this fun conversation!
In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 10/20/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati. PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank. In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case. SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions. He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line? PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions. However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed. To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case. Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond. So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma. Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line. Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line. And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here. SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan. So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products? PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel. For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion. Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case. Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression. To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data. But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely. So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed. SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area. Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry. He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now? PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data. To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor. While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that. However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy. When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently. While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described. SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials. PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy. The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110. So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy? SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors. So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells. So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression. During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy. Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation. There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV. PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients. And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma. The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma. So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma? SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be. Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail. So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement. And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside. I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment. So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed. PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions? In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend. SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle. And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity. Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important. PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings? SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy. The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant. PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms. So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan. I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast. SONALI SMITH: Thank you. It's been a pleasure to speak with you today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.
On the first half of today's show, Dawn and Ray welcome Beth Knobbe, Community Engagement Manager – Catholic Relief Services to discuss CRS projects including how Covid has affected the social needs of people around the world. Greg Schleppenbach, Associate Director of the Pro-life Secretariat at the United States Conference of Catholic Bishops, joins to discuss proposed legislation that could force taxpayer funded abortion, and then Ray and Dawn talk about Respect Life Month and its theme – St Joseph, Defender of Life. www.crs.org www.respectlife.org www.respectlifechicago.org
這毋是哈伯太空望遠鏡 最近翕 ê 遠方星系雲。這个發光 ê 氣體塗粉雲 tī 8 月 29 透早，予太空海岸 ê 觀星者目睭褫金金看甲。這張速翕 是透早 3:17 tī Florida 州 Titusville ê 太空景色公園翕 ê。這是 SpaceX 獵鷹 9 號火箭發射 3 分鐘了後翕 ê。伊當 leh 執行 CRS-23 任務，這个任務主要是欲提供國際太空站補給。伊有翕著浮 tī 太空 ê 光煙 kah 廢氣。這是 ùi tī 夜空 peh-升、脫離 ê 第一節 kah 第二節火箭噴--出來 ê。下跤 ê 光點是第二節火箭，伊繼續 leh 踅 低地球軌道。面頂 ê 光點是火箭第一節，這馬當 leh 推捒燃燒。第一節火箭推捒轉來，嘛第一擺降落 tī 上新 ê 自主無人船，煞-loài 才閣駛去大西洋。這是一擺短短 ê 重力降落行動。 ——— 這是 NASA Astronomy Picture of the Day ê 台語文 podcast 原文版：https://apod.nasa.gov/ 台文版：https://apod.tw/ 今仔日 ê 文章： https://apod.tw/daily/20210904/ 影像：Dennis Huff 音樂：PiSCO - 鼎鼎 聲優：阿錕 翻譯：An-Li Tsai (NCU) 原文：https://apod.nasa.gov/apod/ap210904.html Powered by Firstory Hosting
Gryphon opens the episode with a Scramble meet update, the first in-person meet for PNW Quizzing in about a year and a half. Then Scott and Gryphon discuss all sorts of reference question philosophies. The dynamic duo discuss writing reference questions and how it may be easier to write more CRs than CVRs. They then dive into the notion of "split MAs" and why these may be good or bad. How "small" of a word or phrase should be considered for use in a reference question? What's the difference between "Of the what?" and "I am what?" in terms of question quality. As always, email questions and comments to email@example.com and follow us on Twitter: @InsideQuizzing. Chat in near-real-time on the #inside-quizzing Slack channel. The CBQZ web-based Bible Quizzing application is hosted at: https://cbqz.org/app
Nikki Morgan, CRS Data's MLS Tax Suite sales executive and product expert, sits down with Casie Conlon, CEO of the Central Oregon Association of REALTORS®. The two go deep and get honest about the challenges, hard work and rewards that come when searching for new MLS vendors. Casie has explored and partnered with multiple MLS vendors during her career, including bridging needs across MLSs that have joined forces and entered into a data share. Nikki and Casie take a trip back in time to revisit how MLSs have demoed and tested products over the years and managed a successful conversion experience. Casie offers insights to help make sure you don't miss CE training opportunities, and how to create feedback processes to optimize vendor partnerships. Together, they explore how to find value in the communities you serve and customize your platform experiences across geographical regions. Whether it's asking the tough questions, demo'ing thoughtfully, or exploring unique styles of training, Casie delivers rich insights and advice.
"The Professor" Pritch Pritchard, APR & Fellow PRSA challenges co-host and Golding Group CEO Kyle Golding to a philosophical debate on the Friedman Doctrine: The Social Responsibility of Business is to Increase Its Profits. Friedman is known as one of the most influential economists of the 20th century. The Friedman doctrine has been very influential in the corporate world but has also attracted criticism. We go deep and wide in the back-and-forth discussion. Reference: https://en.wikipedia.org/wiki/Friedman_doctrine. The pair also discuss the Top 4 Corporate Social Responsibility (CSR) Trends To Watch In 2021. Reference article: https://everfi.com/blog/community-engagement/corporate-social-responsibility-trends. On every #NeoMarketing podcast, we discuss best practices, the latest trends and modern techniques for professional business communications including advertising, marketing, digital channels, social media, public relations and alternative options. https://bit.ly/NeoMarketingSubscribe. On the #NeoMarketing podcast, The Golding Group partners Kyle Golding and Pritch Pritchard, APR discuss best practices, latest trends and modern techniques for professional business communications including advertising, marketing, digital channels, social media, public relations and alternative options. Educational, informative and (hopefully) entertaining. Subscribe to the #NeoMarketing podcast: iTunes https://bit.ly/TheGoldingGroup Videos on YouTube https://bit.ly/GoldingGroupYouTube Spotify https://bit.ly/NeoPodcast (Login First) iHeartRadio https://bit.ly/NeoMarketingPod Spreaker https://www.spreaker.com/user/thegoldinggroup Google Podcast https://bit.ly/NeoMarketingGP Podchaser https://bit.ly/NeoPodchaser Pod Link https://pod.link/1275659816 Deezer https://bit.ly/NeoPodDeezer Podcast Addict https://bit.ly/NeoPodAddict To contact us for advice, assistance or collaboration https://thegoldinggroup.com/contact-us/
Spaceflight news— NASA and the Giant Budget Reconciliation (spacenews.com)— Starlink antennas again (spacenews.com) — Thanks to Ben Hallert for the TCM! (twitter.com/chairboy)— Chang'e 5 returned to the Moon (spacenews.com) — Trajectory animation (twitter.com/coastal8049) — Possible TCM Sunday 9/12, or maybe not (https://twitter.com/coastal8049)Short & Sweet— DOD wants to go nuclear (spacenews.com) (diu.mil)— James Webb Space Telescope launch pushed to December (space.com) (planetary.org) (spacenews.com)— Smoke detected in Zvezda module (reuters.com)Questions, comments, corrections— Anonymous source: Different ranges have different fts requirements. Federal ranges have fts handled by the space wing. Commercial range - kodiak - uses white sands missile range on contract as flight safety— Asif Sadiqi's book “Beyond Earth: A Chronicle of Deep Space Exploration 1958-2016” is free for download! (twitter.com/historyasif)This week in SF history— 18 Sept, 2013. Cygnus Demo mission launches (nasa.gov) (en.wikipedia.org) — Orbital Sciences (now NG) won their CRS contract in 2008. (spaceflight101.com) (en.wikipedia.org) (PDF: nasa.gov)— Next week (9/21 - 9/27) in 2011: You ares on fire!
Armond & Doc continue on this week by beginning their track-by-track breakdown of Drake's new album 'Certified Lover Boy' as only CRS can. To hear the rest of the review, along with a lot more, head to patreon.com/crspodcast.
Armond & Doc are back and are going in-depth (in true CRS fashion) on Kanye West's 'Donda'. In Part 1 we cover the lead up to the album and start our track-by-track review. To hear the rest of the review, along with full episodes of previous episodes, join the Patreon at patreon.com/crspodcast.
Armond & Doc are back to begin their break down of the third and final public listening party for Kanye's newly released 'Donda' as only CRS can. To hear the rest of the episode, become a Patreon subscriber at patreon.com/crspodcast.Note: This was recorded the same morning that the album was released, and while we definitely talk about the music and what we like, the in-depth album review is coming later this week.
Welcome everyone to the Reel Film Nerds podcast! Today Matt and Mike break down a trippy sci-fi noir film Reminiscence starring Hugh Jackman and Thandiwe Newton. Topics more interesting than this film include CRS, The Office, and Red Hot Chili Peppers' concerts. There is not a whole lot to say about Reminiscence. It is not only difficult to discuss without spoiling the movie but it is also a really long and at times boring film. There are a lot of great concepts at work here. Wonderful world building, a modern-ish noir, and Hugh Jackman acting his ass off. In the end though Reminiscence just doesn't deliver. It is not a horrible movie but it's not a great one either. Matt thinks Reminiscence is worth a watch if you have HBO Max and nothing else is on. He awards the film an average rating of 3 out of 5 Reels. Mike on the other hand really did not like this movie and can't recommend you to waste your time on it. He gives Reminiscence 2 out of 5 Reels. It's here, it's finally here!! Candyman (2021) is hitting the theaters August 27 after a more than a year hiatus, and Mike and Matt will be there! Who else is excited for Jordan Peele's sequel to a horror classic? Thank you for your continued support of our podcast and we will chat at you next week. If you have a film you would like Matt and Mike to review, email us at firstname.lastname@example.org You can find us on all things social such as YouTube, Facebook, Instagram, and Twitter. Why not join our Facebook Fan Group so you can yell at Mike and Matt from the comfort of your keyboard while talking about films. We also have an old fashioned website where you can watch trailers, read the host's bios, listen to the podcast, and get a ton more info on the movies we review. http://www.ReelFilmNerds.com Thank you for liking, subscribing, rating, reviewing, and telling your friends about our podcast. Finally go out and catch as many movies as you can!
This episode is a compilation episode! I'm learning to DJ to my own standards and i'm bringing you along with me. Today's mix is 45 minutes of amazing songs and artists - MIXED by DJ DevVv. Also btw, Brooke found the engagement ring I was gonna surprise her with. Whooptyfuckingdo. BUT, she still doesn't know when its happening so that's a plus right? RIGHT? CRS 12 Tracklist - Final Cut 1) Skeler & Heimanu - Arcadia 2) Skeler & Heimanu - Arcadia (Heimanu Remix) 3) Marshmello ft Megan Thee Stallion & Nitti Gritti - Bad Bitches 4) Armin Van Buuren ft Jennifer Rene - Fine Without You 5) Issam Alnajjar ft Loud Luxury - Turning Me Up 6) MINESWEEPA - Faces ft Tasha Baxter 7) JOYRYDE - Damn ft Freddie Gibbs 8) Juicy J ft Pooh Shiesty - Tell em No 9) Mike Hawkins - I Want Your Soul 10) Crankdat ft Hyro the Hero - Monster 11) Ashnikko - Slumberparty (Anna Lunoe Remix) 12) COBRAH - TEA 13) Sage Armstrong ft Karra - Dancing $hoes (Black V Neck Remix) 14) Tchami ft Gunna - Praise 15) Tchami ft Gunna - Praise (Malaa Remix) 16) Valentino Khan ft Nitti Gritti - Your Body 17) Hardwell ft Quintino - Mi Gente 18) Brondo - Chasing Paper 19) INZO - Wonder 20) Yellow Claw ft Riatek - Can't Get Enough 21) Slumberjack - RA 22) Buku - Align 23) Burna Boy - On the Low 24) Barbatuques ft Clozee - Baiana (Clozee Remix) 25) Valentino Khan ft wifisfuneral & YBN Almighty Jay 26) Stevie Stone - Run It
Gryphon and Scott open with a PNW Quizzing leadership meeting announcement and some good news about the upcoming season. Then the dynamic duo turn their attention to reference questions in their quest to answer all your reference questions questions. What are they? What's the point and value of them? What are the differences from other types? What's the history of CRs versus CVRs? What's the best strategy for preparing and answering reference questions? What's a "50/50" reference question? What does "Similar" mean, and why should we care? And what does "Determining reference word or phrase" mean? As always, email questions and comments to email@example.com and follow us on Twitter: @InsideQuizzing. Chat in near-real-time on the #inside-quizzing Slack channel. The CBQZ web-based Bible Quizzing application is hosted at: https://cbqz.org/app
After an eventful weekend, Kris, Jez, Phil and Rich get together to round up all the Ligue 1 action, including goals, red cards, bottles, pitch invasions, presidents grabbing the microphone, the CRS showing up, and upcoming disciplinary issues. They look at the 'big' teams having a bit of a mare, the players who impressed, and some mild transfer chat.
Step in to the studio with reggae pioneer and cultural ambassador Hopeton Brown. Log on to discuss the message behind the music. Music is divine, universal and a tool to empower the youths. Wednesdays - 9 - 12 Midnite EST Dial in (661) 467-2407. The show focuses on the “message behind the music” with a moral obligation to educate the youths.
In our newest episode, sales executive and product expert Nikki Morgan sits down with leaders from Northern Nevada Regional MLS; including Andrew Cristancho, director of marketing; and George Pickard, CEO. In both theory and practice, they explore how their powerhouse team has developed and grown a tech-forward, innovative MLS. They have helped spearhead a movement to empower their MLS members by leveraging today's newest technologies, thoughtful partnerships, and forward-thinking practices. With Nikki, they consider what it takes to build a meaningful MLS that prioritizes truly listening to their members. Join us as they revisit what it's been like to expand their MLS's resources for members through the years -- and what the future looks like as they continue to put members first.
Podcast Announcements 1) CRS 11 has been posted on my Soundcloud page so if you enjoyed the music from the last 2 weeks and wanna find it all in ONE place go to soundcloud.com/devvvmusic/castle-rock-streams-11 for a 40 minute mix. 2) I'm opening up my studio for podcast production. If you need a podcast recorded, edited, or managed in any way shape or form, feel free to HMU at firstname.lastname@example.org and we can get to cracking. Also check out my Fiverr Page! Which will be posted next week. 3) Finally, DevVv Talks HAS A NEW EMAIL, but no ones emailed us yet so be the first! Feel free to submit news articles, new artists, new genres, new songs, or just wanna roast one of the show hosts, EMAIL US. Mix 1 Tracklist: 1) Skeler ft Heimanu - Arcadia 2) Skeler ft Heimanu - Arcadia (Heimanu Remix) 3) Marshmello & Megan THEE Stallion - Bad Bitches 4) Armin Van Buuren & Jennifer Rene - Fine Without You 5) Issam Alnajjar ft Loud Luxury - Turning Me Up Podcast Topics: S'Wizard & Marvelous got married recently; Jeff Bezos Goes to Space (thanks Amazon workers); Texas Proposes a horrible education bill prompting the gang to discuss "Critical Race Theory" Mix 2 Tracklist 1) MINESWEEPA ft Tasha Baxter - Faces 2) JOYRYDE - Damn ft Freddie Gibbs 3) Juicy J ft Pooh Shiesty - Tell Em No 4) Mike Hawkins - I Want Your Soul 5) Crankdat ft Hyro the Hero - Monster PODCAST NEWS: 1) 18,000 Anti - Sex cardboard beds installed in Olympic Village(who's "sleeping" in these beds? What about peak performance? Are they still going to hand out condoms?) 2) Bucks Win the NBA Championship (Giannis scores 50 and only misses one free throw; Chris Paul & Devin Booker finally run into defensive troubles) + Giannis Clip**** 3) A program that began in Oregon with the purpose of replacing Police with trained Social Workers continues making strides in Denver. Denver's "Pivot From Police" increases resources; gains nationwide attention. Song of the episode you should download belongs to: Kiana Ledé with the track "Second Chances" - I looped the ending of the song into the beginning so you can hear the raw emotion twice. If you are being abused by a narcissist, or know someone who is, the only way to protect yourself or them is to simply not communicate with your abuser in any way, shape, or form. This track exemplifies moving beyond someone who doesn't see you for your true value. We've got content, you got ears. Lets get it!
Massive upheaval in the Caribbean is making waves ... First we check in with Catholic Relief Services. The Baltimore-based nonprofit is doing its best to administer relief to the people of Haiti amid political turmoil, gang violence and hurricane aftereffects. Akim Kikonda, CRS country representative in Haiti, describes what they're up against: “Having so many crises at the same time is absolutely unique. And I'm extremely impressed with the level of resiliency that I'm seeing in the population.” Plus, American University Professor William LeoGrande, an expert in US-Cuba relations, breaks down the politics behind events playing out on the island off Florida's coast and the weight of U.S. policy. Links: Catholic Relief Services, Prof. LeoGrande articles in The Nation, Responsible StateCraft, Daily Beast. See omnystudio.com/listener for privacy information.
In this podcast episode, Donna Catamero, ANP-BC, OCN, CCRC, highlights practical considerations for integrating anti-BCMA–targeted therapy into clinical practice for patients with multiple myeloma after multiple relapses. Don't forget to listen to part 1 of this series with a discussion on other novel treatment options by Tiffany Richards, PhD, ANP-BC, AOCNP, Nurse Practitioner at the University of Texas MD Anderson Cancer Center.Presenter: Donna Catamero, ANP-BC, OCN, CCRCAssociate Director, Myeloma Translational ResearchThe Mount Sinai Health SystemNew York, New YorkCE/AAPA credit available by visiting the online program: https://bit.ly/3ee9IvsLink to full program, including downloadable slidesets: https://bit.ly/3ee9Ivs
In this episode, Caron A. Jacobson, MD; Jae H. Park, MD; and Noopur Raje, MD, answer audience questions from a live CCO webinar focused on current best practices and emerging strategies in CAR T-cell therapy, with questions including:At what time in the treatment journey should CAR T-cell therapy be considered?How to select among 3 approved products for relapsed/refractory large B-cell lymphoma?How is CAR T-cell therapy best used for multiple myeloma?What qualities of bridging therapy are most preferred?When do patients receiving CAR T-cell therapy need COVID-19 or other vaccinations? How are steroids optimally used in managing CAR T-cell therapy–related toxicities?Presenters:Caron A. Jacobson, MDAssistant ProfessorDivision of Medical OncologyDepartment of MedicineHarvard Medical SchoolDana-Farber Cancer InstituteBoston, MassachusettsJae H. Park, MDAssociate Member Leukemia Service and Cellular Therapeutics Center Memorial Sloan Kettering Cancer CenterNew York, New YorkNoopur Raje, MDDirectorCenter for Multiple MyelomaMassachusetts General Hospital Cancer Center Professor of MedicineHarvard Medical SchoolBoston, MassachusettsContent based on an online CME program supported by an educational grant from Bristol-Myers Squibb.Link to full program:https://bit.ly/3BfbEOf
aribbean Radio Show annual PALAS Telethon helping Jamaica's needy students Greetings #CRS family, tomorrow is the annual #PALAS (Peace and Love Academic Scholarship) radio Telethon. This is an annual fundraising event for our Scholarship program. 12 #radio stations will participate. CRS will broadcast 4-5 pm EST. We are asking all CRS radio #hosts to call in and donate and support this event. A Full Scholarship is #$350 USD. If you cannot do a full scholarship, please donate what you can but #donate something. This is for a good cause and it is tax-deductible. I am attaching information. Please post on your social #media. Please acknowledge receipt of this text. I will also follow up with a phone call. Let's endorse giving back to the youths. Call in 661-467-2407
In this podcast episode, Tiffany Richards, PhD, ANP-BC, AOCNP, highlights practical considerations for integrating novel treatments— selinexor, venetoclax, and melphalan flufenamide—into clinical practice for patients with multiple myeloma after multiple relapses. Check back to hear part 2 of this series with a discussion on BCMA-targeted therapy by Donna Catamero, ANP-BC, OCN, CCRC, Associate Director of Myeloma Translational Research at the Mount Sinai Health System.Presenter: Tiffany Richards, PhD, ANP-BC, AOCNPNurse PractitionerDepartment of Lymphoma/MyelomaThe University of Texas MD Anderson Cancer CenterHouston, TexasCE/AAPA credit available by visiting the online program: https://bit.ly/3ee9IvsLink to full program, including downloadable slidesets: https://bit.ly/3ee9Ivs
Short chain fatty acids: An 'ace in the hole' against SARS-CoV-2 infection Scientists find that short chain fatty acids can be used to reduce susceptibility to SARS-CoV-2 infection and mortality from COVID-19 University of Fukui (Japan), July 14, 2021 Humans are no stranger to coronavirus (CoV) pandemics. Just like SARS-CoV-2 (the virus that causes COVID-19), another member of the coronavirus family--SARS-CoV--caused the severe acute respiratory syndrome (SARS) epidemic across parts of Asia in 2003. But, its spread was contained way faster than COVID-19. So, what makes SARS-CoV-2 so contagious? Both SARS-CoV and SARS-CoV-2 viruses bear "spike proteins" which get inside our cells by binding to a protein called angiotensin-converting enzyme 2 (ACE2) that is found in our cells. However, the SARS-CoV-2 spike (S) protein has been found to have a higher binding affinity (10 to 20 times that of SARS-CoV) to ACE2, thus establishing a link between the pathogen and the protein. Interestingly, recent studies have shown that patients with COVID-19 who have rhinosinusitis (i.e., inflammation of the nose) have a low risk of hospitalization. Moreover, the expression of ACE2 was reduced in patients with rhinosinusitis. Coincidentally, another study has shown that short-chain fatty acids (SCFAs), produced by bacteria in the gut have beneficial effects in allergy and viral infections. These separate findings prompted an investigation of the effect that SCFAs in the nasal cavity against SARS-CoV-2 infection by scientists from the University of Fukui, Japan, led by Dr. Tetsuji Takabayashi. In a new study published in the American Journal of Rhinology & Allergy, the scientists attempted to understand the effect of SCFAs on ACE2 expression in the nasal passage, and the potential impact on COVID-19 infection. "This is the first report that short-chain fatty acids (SCFAs) effectively reduce the ACE2 levels in human airway epithelial cells," remarks Dr. Takabayashi. To understand the status of ACE2 expression in patients with allergies, the researchers studied the levels of ACE2 in the inner lining of the nose in patients with seasonal allergic rhinitis induced by Japanese cedar pollen (SAR-JCP) and chronic rhinosinusitis (CRS). Using techniques like real time-PCR to quantify the expression of ACE2, the researchers found that there was no increase in ACE2 expression in in patients with SAR-JCP, whereas it was decreased in patients with CRS. To better understand the effect of SCFAs on ACE2 expression, the researchers cultured nasal epithelial cells and exposed them to either SFCA and double-stranded RNA (similar to the nuclear material found in some viruses and known to enhance ACE2 expression). Upon examining the expression of ACE2, the researchers saw that the SFCAs had suppressed ACE2 expression in the presence of the RNA as well. These results suggest that SFCAs has potential therapeutic applications against COVID-19. Dr. Takabayashi explains, "The nasal mucosa exhibits the highest ACE2 expression among human organs and hence is a prominent target of original infection. Therefore, the development of strategies to downregulate ACE2 expression in nasal epithelial cells could reduce SARS-CoV-2 transmission and be useful as a novel therapeutic approach." The team's timely findings will certainly aid in our fight against COVID-19. Flavonoids may slow Alzheimer onset Tufts University Human Nutrition Center, July 13, 2021 The following information was released by the U.S. Department of Agriculture: According to the U.S. Centers for Disease Control and Prevention, an estimated 5.8 million Americans aged 65 or older live with Alzheimer's disease, and that number is projected to nearly triple by 2160. Fortunately, USDA-funded research may have found a tasty way to slow disease onset. A study published in the American Journal of Clinical Nutrition suggests that diets high in flavonoids may protect cognitive health. Flavonoids are plant nutrients known for their antioxidant, antiviral, and anticancer properties and are found in berries, tea, dark chocolate, and other foods. "Alzheimer's disease is a significant public health challenge," said Paul Jacques, nutritional epidemiologist at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston. "Given the absence of drug treatments, preventing Alzheimer's disease through a healthy diet is an important consideration." Jacques's study, which followed 2,809 people for nearly 20 years, revealed that diets high in fruits and vegetables showed significant promise to quell the onset of Alzheimer's. "Our study showed that individuals with the highest intakes of flavonoids were more than 50% less likely to develop Alzheimer's disease, relative to those with the lowest intakes," he said. "Plant foods, such as vegetables, fruits, nuts, and seeds are good sources of flavonoids." According to Jacques, flavonoid-rich diets help more than just Alzheimer's disease and related dementia. "The bottom line is that there are many reasons to consume a healthy diet, including lower risks of cardiovascular disease and some cancers. We can now add protection of cognitive health and prevention of Alzheimer's disease to that list." Mitochondria malfunction shown to be the major cause of Parkinson's University of Copenhagen (Denmark), July 9, 2021 12,000 people in Denmark and 7 to 10 million people worldwide suffer from Parkinson's Disease (PD). It is the second most common neurogenerative disorder of aging and the most common movement disorder, but the cause of the disease is largely unknown. In a new study, researchers from the University of Copenhagen show that the most common form of the disease, encompassing 90 to 95 percent of all Parkinson's Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates the nerve cell's powerhouse, the mitochondria. "Just like when people eat, cells take what they need and get rid of the rest waste products. But if our brain cells have this specific kind of signaling blockage, it means that the powerhouse of the cell—mitochondria—cannot get cleaned up after being damaged," explains corresponding author and group leader Professor Shohreh Issazadeh-Navikas at the Biotech Research & Innovation Centre. The blockage leads to an accumulation of high amounts of damaged mitochondria, while not being able to produce enough energy for the cells. It causes neurons to gradually die, which is the reason for the development of Parkinson's Disease symptoms, and why it leads to dementia. The blockage is caused by a dysregulation of the immune genes, more specifically a pathway called type 1 interferon, which is normally important for fight against viruses, but now we show that it is also responsible for regulating the energy supply of the nerve cells. "Every part of our body needs to be regulated. We get a signal to stop eating, when we are full, and the same thing happens everywhere else in our body. If we get an infection, parts of our body need to fight it and stop it from replicating. But when the infection is cleaned up, the signal should subside. This is the job of a protein called PIAS2. That causes the blockage of the type 1 interferon-pathway, and when the infection is over, the blockage should stop and go back to normal. But that does not seem to be the case in patients with Parkinson's Disease. We further demonstrate that this dysregulation leads to a defect in the mitochondrial energy supply, as mentioned before," says Issazadeh-Navikas. These pathways are very important for brain functions, but they are also associated with microbial and virus recognition. For example, they are very important for fighting COVID-19, and a mutation in the related gene has been shown to be linked to a deadly outcome after contracting COVID-19. The researchers combined and analyzed four data sets, which studied neurons from brains with Parkinson's Disease and looked at what type of genes they express. They then looked at which gene patterns were disturbed in patients with Parkinson's Disease and especially those who had also developed PD with dementia. In order to test the results, the major findings of the combined data was tried in three different mouse models using a negative regulator of the type I interferon pathway, PIAS2, which had been identified from the patients study as one of the key proteins linked to the progression of Parkinson's Disease and dementia. "We show that a high accumulation of the PIAS2-protein is what is causing the blockage in the pathway, which should have activated the processes responsible for removing damaged protein and mitochondrial garbage," says Issazadeh-Navikas. "The accumulation of damaged mitochondrial mass further leads to increase of other toxic proteins. So when we compare patients to same-aged healthy patients without Parkinson's Disease, we see that this PIAS2-protein is highly expressed in the neurons, which is why this pathway should be evaluated for potential roles in the other forms of familial Parkinson's Disease that we have not studied here." The researchers hope the study will encourage research to counteract the pathway blockage, which could have a beneficial impact on the disease and towards preventing dementia. In the next stages, the Issazadeh-Navikas group will study how the pathwaycontributes to neuronal homeostasis and survival, as well as how its dysregulation causes neuronal cell death. Combining plant-based diet and a healthy microbiome may protect against multiple sclerosis Metabolism of isoflavone by gut bacteria protects mice from MS-like inflammation University of Iowa, July 13, 2021 A new University of Iowa study suggests that metabolism of plant-based dietary substances by specific gut bacteria, which are lacking in patients with multiple sclerosis (MS), may provide protection against the disease. The study led by Ashutosh Mangalam, PhD, UI associate professor of pathology, shows that a diet rich in isoflavone, a phytoestrogen or plant-based compound that resembles estrogen, protects against multiple sclerosis-like symptoms in a mouse model of the disease. Importantly, the isoflavone diet was only protective when the mice had gut microbes capable of breaking down the isoflavones. The findings were published July 9 in Science Advances. "Interestingly, previous human studies have demonstrated that patients with multiple sclerosis lack these bacteria compared to individuals without MS," Mangalam says. "Our new study provides evidence that the combination of dietary isoflavones and these isoflavone metabolizing gut bacteria may serve as a potential treatment for MS." Isoflavones are found in soybeans, peanuts, chickpeas and other legumes. The study also found that mice fed the isoflavone diet have a microbiome that is similar to the microbiome found in healthy people and includes the bacteria which can metabolize isoflavones. Conversely, a diet lacking isoflavones promotes a microbiome in mice which is similar to one observed in patients with MS and lacks beneficial bacteria that can metabolize isoflavone. Multiple sclerosis is an autoimmune disease of the brain and spinal cord where the immune system attacks the protective coating surrounding nerve fibers. The symptoms of this disease include muscles weakness, balance issues, and problems with vision and thinking. While there are treatments that slow down the disease, there is currently no cure for MS. Although the exact cause of MS is unknown, a complex interaction between genetic and environmental factors are thought to initiate the disease. Recently, the gut microbiome--the trillions of gut bacteria the live inside human intestines--has emerged as a potential environmental factor that contributes to MS. In prior work, Mangalam and colleagues demonstrated that there are significant differences between the gut microbes of patients with MS and people without MS. Specifically, patients with MS lacked bacteria that are able to metabolize isoflavones. Although role of gut microbiome in human diseases such as MS is being appreciated, the mechanism through which these gut bacteria might influence the disease is poorly understood. In the current study, Mangalam's team, including first author Samantha Jensen, a UI graduate student in immunology, found that the bacteria that are lacking in patients with MS are able to suppress inflammation in a mouse model of MS. The team compared the effects of an isoflavone diet and an isoflavone-free diet on disease in the mouse model of MS. They found that the isoflavone diet led to disease protection. However, when the team placed the mice on the isoflavone diet but removed the isoflavone-metabolizing gut bacteria, the isoflavone diet was no longer able to protect against MS-like symptoms. When the bacteria were reintroduced, the protective effect of the isoflavone diet was restored. Furthermore, the team was able to show that a specific isoflavone metabolite called equol, which is produced by the gut bacteria from isoflavone, is also able to provide protection against disease. "This study suggests that an isoflavone diet may be protective so long as the isoflavone metabolizing gut bacteria are present in the intestines," say Mangalam, who also is a member of the Iowa Neuroscience institute and Holden Comprehensive Cancer Center. How a Mediterranean diet could reduce osteoporosis University of East Anglia (UK), July 12, 2021 Eating a Mediterranean-type diet could reduce bone loss in people with osteoporosis - according to new research from the University of East Anglia. New findings published today show that sticking to a diet rich in fruit, vegetables, nuts, unrefined cereals, olive oil, and fish can reduce hip bone loss within just 12 months. The study is the first long-term, pan-European clinical trial looking at the impact of a Mediterranean diet on bone health in older adults. More than 1,000 people aged between 65 and 79 took part in the trial, and volunteers were randomised into two groups - one which followed a Mediterranean diet and a control group which did not. Bone density was measured at the start and after 12 months. The diet had no discernible impact on participants with normal bone density, but it did have an effect on those with osteoporosis. People in the control group continued to see the usual age-related decrease in bone density, but those following the diet saw an equivalent increase in bone density in one part of the body - the femoral neck. This is the area which connects the shaft of the thigh bone to its rounded head, which fits in the hip joint. UK study lead Prof Susan Fairweather-Tait, from UEA's Norwich Medical School, said: "This is a particularly sensitive area for osteoporosis as loss of bone in the femoral neck is often the cause of hip fracture, which is common in elderly people with osteoporosis. "Bone takes a long time to form, so the 12-month trial, although one of the longest to date, was still a relatively short time frame to show an impact. So the fact we were able to see a marked difference between the groups even in just this one area is significant." The EU-funded trial, led by the University of Bologna, was completed by 1142 participants recruited across five centres in Italy, the UK, the Netherlands, Poland and France. Those following the Mediterranean diet increased their intake of fruits, vegetables, nuts, unrefined cereals, olive oil, and fish, consumed small quantities of dairy products and meat and had a moderate alcohol intake. People in the intervention group were provided with foods such as olive oil and wholemeal pasta, to encourage them to stick to the diet, and were also given a small vitamin D supplement, to even out the effects of different levels of sunlight on vitamin D status between the participating countries. At the start and end of the trial, blood samples were taken to check for circulating biomarkers. Bone density was measured in over 600 participants across both groups at the lumbar spine and femoral neck. Of these participants, just under 10% were found to have osteoporosis at the start of the study. Co-researcher from UEA, Dr Amy Jennings said: "Although this is a small number it is sufficient for the changes in femoral neck bone density between the two groups to be statistically significant. "Those with osteoporosis are losing bone at a much faster rate than others, so you are more likely to pick up changes in these volunteers than those losing bone more slowly, as everyone does with age. "With a longer trial, it's possible we could have picked up changes in the volunteers with normal bone density. However, we already found it quite challenging to encourage our volunteers to change their diet for a year, and a longer trial would have made recruitment more difficult and resulted in a higher drop-out." The researchers would now like to see a similar, or ideally longer, trial in patients with osteoporosis, to confirm the findings across a larger group and see if the impact can be seen in other areas of the body. If the condition could be mitigated through diet, this would be a welcome addition to current drug treatments for osteoporosis, which can have severe side effects. But in the meantime, say the researchers, there is no reason for those concerned about the condition not to consider adapting their diet. "A Mediterranean diet is already proven to have other health benefits, reducing the risk of cardiovascular disease, Parkinson's, Alzheimer's and cancer," said Prof Fairweather-Tait. "So there's no downside to adopting such a diet, whether you have osteoporosis or not." 'A Mediterranean-like dietary pattern with vitamin D3 (10 μg/day) supplements reduced rate of bone loss in older Europeans with osteoporosis at baseline: results of a one year randomised controlled trial' is published in the American Journal of Clinical Nutrition . Rishi mushroom promotes sleep through a gut microbiota-dependent and serotonin-involved pathway Hang-zhou Medical College (China), July 10, 2021 According to news reporting out of Zhejiang, People's Republic of China, research stated, “Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative tranquilizing effects. However, the component of G. lucidum that promotes sleep has not been clearly identified.” Our news journalists obtained a quote from the research from Hangzhou Medical College, “Here, the effect and mechanism of the acidic part of the alcohol extract of G. lucidum mycelia (GLAA) on sleep were studied in mice. Administration of 25, 50 and 100 mg/kg GLAA for 28 days promoted sleep in pentobarbital-treated mice by shortening sleep latency and prolonging sleeping time. GLAA administration increased the levels of the sleep-promoting neurotransmitter 5-hydroxytryptamine and the Tph2, Iptr3 and Gng13 transcripts in the sleep-regulating serotonergic synapse pathway in the hypothalamus during this process. Moreover, GLAA administration reduced lipopolysaccharide and raised peptidoglycan levels in serum. GLAA-enriched gut bacteria and metabolites, including Bifidobacterium, Bifidobacterium animalis, indole-3-carboxylic acid and acetylphosphate were negatively correlated with sleep latency and positively correlated with sleeping time and the hypothalamus 5-hydroxytryptamine concentration. Both the GLAA sleep promotion effect and the altered faecal metabolites correlated with sleep behaviours disappeared after gut microbiota depletion with antibiotics.” According to the news editors, the research concluded: “Our results showed that GLAA promotes sleep through a gut microbiota-dependent and serotonin-associated pathway in mice.” Vitamin C found to block growth of cancer stem cells, says peer reviewed study University of Salford (UK), July 8, 2021 Increasingly, researchers are discovering the role played by cancer stem cells in the growth and spread of the disease. In groundbreaking new research, vitamin C showed its ability to target cancer stem cells and stop their growth – preventing the recurrence of tumors. Although mainstream medicine has been slow to accept the cancer-fighting properties of vitamin C, the exciting results of this study could help to change that. In a newly-published study conducted at the University of Salford in Manchester, vitamin C demonstrated its power to stop tumors in their tracks by interfering with cancer stem cell metabolism – suppressing their ability to process energy for survival and growth. Cancer stem cells are responsible for triggering tumor recurrence, and promoting their growth and metastasis. Researchers believe that cancer stem cells give cancer its ability to resist chemotherapy and radiation – the reason for treatment failure in advanced cancer patients. The study, helmed by researchers Michael P. Lisanti and Gloria Bonucelli, was published last month in Oncotarget, a peer-reviewed journal. Peer-reviewed studies are considered the gold standard of scientific research. The study was the first to explore the effects of vitamin C on cancer stem cells – and provided the first evidence that vitamin C, in the form of ascorbic acid, can target and kill them. In a side-by-side comparison of seven different substances, vitamin C even outperformed an experimental cancer drug. The team investigated the impact on cancer stem cells of seven different substances. Three were natural substances, three were experimental drugs, and one was an FDA-approved clinical drug that is widely used. The natural products studied, along with vitamin C, were silibinin – derived from milk thistle seeds – and caffeic acid phenyl ester – or CAPE – derived from honeybee propolis. The experimental drugs were actinonin, FK866 and 2-DG, and the clinical drug was stiripentol. Researchers noted that vitamin C destroyed cancer stem cells by inducing oxidative stress. And, the vitamin performed this process ten times more effectively than 2-DG. Vitamin C used two different mechanisms of action to attack cancer stem cells. It worked as a pro-oxidant in cancer cells, depleting them of the antioxidant glutathione and causing oxidative stress and apoptosis – or cell death. It also inhibited glycolysis, which is the process that creates energy production in cell mitochondria. By inhibiting glycolysis, vitamin C inhibited mitrochondrial protein synthesis in cancer stem cells – while leaving healthy cells unaffected. Both experimental and approved cancer drugs can feature serious adverse effects, including thrombocytopenia – a deficiency of platelets in the blood that can cause bruising and slow blood clotting. They can also induce lymphopenia – a decrease in the body's infection-fighting white blood cells – and anemia, or low red blood cells. And the clinically-approved drug used in the study, stiripentol, can cause severe nausea, vomiting and fatigue. On the other hand, the National Cancer Center reports that high-dose vitamin C has caused very few side effects when used in clinical studies. All seven of the substances tested inhibited the growth of cancer cells to varying degrees – including the non-toxic natural substances. But researchers said the most “exciting” results were with vitamin C. The research team concluded that vitamin C was a “promising new agent,” and called for more study to explore its use as an adjunct to conventional cancer therapies to prevent tumor recurrence and growth. “Vitamin C is cheap, natural, non-toxic and readily available, so to have it as a potential weapon in the fight against cancer would be a significant step,” observed Dr. Lisanti. As in most of the successful studies showing vitamin C's cancer-fighting properties, researchers used high doses of vitamin C, administered intravenously. IV vitamin C therapy is available in some alternative and holistic cancer treatment clinics worldwide. Again, vitamin C was 1,000 percent more effective than 2-DG, an experimental pharmaceutical drug – in targeting cancer stem cells. If vitamin C were developed by big pharma, these results would be shouted from the rooftops and featured in newspaper headlines. Yet, as always, “the powers that be” in mainstream medicine respond with…crickets. The reason; say natural health experts, is all too obvious. As a natural nutrient and vitamin, vitamin C can't be patented, and is inexpensive and easy to obtain. Therefore, there is no incentive for cancer clinics to promote it – when they can instead rake in the profits from chemotherapy. The indifference of conventional medicine to vitamin C is all the more frustrating because the nutrient has been shown to be an effective and non-toxic anti-cancer agent in previous studies, including many conducted by Nobel prize-winning scientist Linus Pauling. Vitamin C has been shown in a Japanese study to cut mortality in cancer patients by 25 percent. In addition, it has inhibited tumors in animal studies, and been shown to kill cancer cells in a wide variety of cancer cell lines. How much longer will the potential of this safe and powerful cancer-fighting nutrient be overlooked?
In this episode, Eric Tivers is joined by Will Curb, MJ Siemens, and ADHD reWired coaches Moira Maybin & Roxie Martin. Barb also joins the panel as the ADHD reWired podcast family takes in and answers the questions from the listeners of the ADHD reWired Podcast. Brendan Mehan, we missed you this month! Every second Tuesday of the month, the ADHD reWired panel takes questions from our listeners live about their ADHD-related topics. Whether it's personal or professional, the panelists are here every single month to ask questions and offer their knowledge and unique perspectives to help ADHD folks find the solutions they need. Thank you for listening to the Q & A session this month. We cover a wide variety of topics and provide creative takeaways, no matter what stage you're in with your diagnosis. Listen in as we discuss your questions and the struggle we all continue working through as we navigate with ADHD. Find the other podcasts on the ADHD reWired Podcast Network: What will you find in this episode? [00:01:43] - Welcomin the ADHD reWired Podcast Family! [00:02:10] - Roxie and Will confirm rumors about their new podcast [00:03:21] - Jane asks, “What can you do when you just cannot get your brain to engage, even if you want to? [00:03:34] - Eric explains how trying to force it doesn't work; he shifts to prioritizing sleep, and his brain doesn't (typically) work with lack of sleep. [00:04:27] - Will says going for a walk and getting movement in is helpful. [00:05:05] - Eric talks about how even though taking breaks is difficult, he always feels better after doing so. [00:05:38] - Moira talks about hormones and how expectations can be managed around hormonal cycles, while Eric mentions her podcast [the ADHD Friendly Lifestyle!] [00:06:37] - Roxie talks about riding on someone's coattails, listens to ADHD-related podcasts & content, and enjoys singing karaoke for a break. [00:07:22] - Eric mentions Adult Study Hall and how a pomodoro dance break was really useful and fun! [00:07:52] - When MJ feels stuck, they talk about reaching out and telling someone, talking with their partner for a break, doing jumping jacks, and taking a pet-parent break. [00:08:53] - Will encourages ADHD folks to write down things that don't work and mentions how scrolling social media doesn't typically work. [00:09:18] - Eric likes video games but doesn't usually stop at just 5 minutes of playing. [00:10:03] - Scott asks about being on Adderall and wonders if his experiences are because of taking medication. [00:10:27] - Eric encourages folks to talk to their doctors and the documented side-effects of stimulant medication. [00:15:50] - Terry wants the panelists to talk about medications, particularly when kids are reluctant and contrary to medical advice. [00: 16:15] - Eric talks about how the research shows that when parents push medication during adolescence, the likelihood of the teens going back to medication as adults is drastically decreased. Eric encourages to allow the teen to make the call, which makes it more likely for them to go back to the medication as adults. [00:17:04] - Eric also encourages parents to read about motivational interviewing. [00:17:56] - Moira encourages parents to include the kids as part of the conversation. [00:20:10] - Eric encourages a healthy-fat high-protein breakfast before giving them their medication and let kids eat when they're hungry. [00:21:07] - Andrew wants to improve his communication skills and wonders if CBT or other methods could be helpful. [00:21:36] - Eric says CBT or DBT could be helpful. [00:22:06] - Mentioned: How to Win Friends and Influence People by Dale Carnegie, and Crucial Conversations by Joseph Grenny and Kerry Patterson [00:23:15] - Will talks about trying different communication models, such as a phone call or text to give the brain time to catch up. [00:24:13] - Eric says to take a break but 23] commit to coming back. [00:25:00] - Roxie realizes trying to get into problem solving before we're ready that we have such a huge breakdown. [00:25:10] - Mentioned: Change Your Questions, Change Your Life by Marilee Adams [00:25:25] - Kristen asks, “How do I lessen my interrupting in group discussions?” [00:25:36] - Moira talks about hyperarousal and treatments that helped her [00:26:03] - Eric and Moira encourage writing stuff down; Eric talks about some coping mechanisms and sitting in the discomfort of silence. [00:27:00] - Will talks about cultural conversational styles across the U.S. [00:27:37] - Suzanne asks about how to respond or having a set of pre-fabricated responses when people make comments about over-planning and other ADHD-related topics, while keeping composed. [00:28:20] - Eric thinks it's cute when someone says, “You'll remember that.” [00:28:42] - MJ admits to being a chronic over-planner and talks about coping mechanisms they've developed with having ADHD. [00:30:23] - MJ encourages being okay with what we do and to give ourselves grace, and “Slow motion is better than no motion! [00:31:47] - Suzanne also asks if a lot of this is internal dialogue and talks about everything she writes down after grocery shopping. [00:32:36] - Eric says, “Do what works for you!” [00:32:48] - Moira talks about being selective with sharing about her ADHD and driving with a GPS is always useful for her. [00:34:20] - Hannah asks about international support for people with ADHD. [00:41:10] - Mentioned: adhd-hub.com / adhdactually.com (not reviewed) [00:41:34] - Elaine asks about “transition dread” [00:42:48] - Roxie asks Elaine some coaching questions [00:45:08] - Elaine talks about food sensitivities [00:45:45] - MJ also asks Elaine some coaching questions and talks about doing new tasks. [00:47:06] - Elaine is reminded of fun things & wonders about doing brand new tasks. [00:47:32] - Eric asks Elaine if there is anything she can let go of and talks about “CRS” [00:48:15] - Eric and Elaine talk about admin work while being self-employed and being seen. [00:48:57] - Eric stresses that it is important that you feel seen and understood by the professionals you are working with and to get people who understand you on your team. [00:49:46] - Eric says he will always need help, and needing help is okay. [00:50:38] - Rob asks if neurotypical folks have the same problems or issues that folks with ADHD have. [00:52:17] - Eric mentions that we may not be fully aware that we do some things better than other people because those things don't feel hard. [00:53:17] - Eric talks about the struggle of putting something in the mail. [00:53:58] - Moira acknowledges that neurotypical people have the same struggles, but that ADHD also affects us socially, at home, and affects our working memory. [00:54:58] - MJ shares their observations about how certain tasks seem much easier for neurotypical folks than ADHD folks. [00:56:05] - Grace asks if coaching would be useful even with a brand-new diagnosis and still earned a PhD [00:56:30] - Eric talks about coping skills, intelligence, and gives kudos for resilience and tenacity. [00:56:58] - All the panelists vote “Yes” to group-coaching for ADHD, no matter what stage or how recent the diagnosis was. [00:57:58] - Jason asks how to go about getting a diagnosis in Canada. [00:58:23] - MJ highly encourages folks to find professionals who specialize in ADHD and why that's important. [00:59:28] - Moira mentions CADDRA and CADDAC who list practitioners in Canada, and the importance of knowing what symptoms to talk about. [01:00:56] - Eric encourages folks to get on a list to see someone even if it's a long wait. [01:02:41] - The panelists circle back to Terry's question about keeping kids accountable without nagging them. [01:03:15] - Barb talks about dry-erase boards and letting her son check things off instead of nagging. [01:03:45] - Eric repeats motivational interviewing - it's a great place to start, and says there is no such thing as failing when we're trying new things. Also mentioned in this episode: Become a of ADHD reWired
Dr. Maya Soetoro-Ng is a peace educator and professor at the University of Hawaii at Manoa. She is also the co-founder of three nonprofits: Ceeds of Peace, The Institute for Climate and Peace, and Peace Studio. The Bravethrough Series brings Maya to the table with changemakers and influencers from the front lines of our communities. Listen to learn new strategies, revisit out assumptions, and challenge ourselves to take action in brave new ways. Guest: Grande Lum, Provost, Menlo College Provost Lum enjoys writing, teaching, and working on issues that help people and communities work together in more constructive ways. Prior to joining Menlo, he was Director of the Divided Community Project (DCP) at the Ohio State University Moritz College of Law. Previously, Grande Lum was nominated by President Barack Obama and confirmed by the Senate in 2012 as the Director of the Community Relations Service (CRS), an agency within the Department of Justice. Before joining CRS, Grande Lum was a clinical professor at the University of California Hastings School of the Law, where he directed the Center for Negotiation and Dispute Resolution. Grande also serves as a senior advisor to the Rebuild Congress Initiative. Resources Inspired by the Conversation - Divided Community Project: https://moritzlaw.osu.edu/dividedcommunityproject/ Within that website here are some additional things worth connecting to Toolkit for leaders - https://moritzlaw.osu.edu/dividedcommunityproject/toolkit-core-page Bridge Initiative offering rapid consultation for communities in addressing conflict: https://moritzlaw.osu.edu/dividedcommunityproject/bridge-initiative/ Campus Academy: https://moritzlaw.osu.edu/dividedcommunityproject/campus-academy-initiative/ Community Academy: https://moritzlaw.osu.edu/dividedcommunityproject/strengthening-democratic-engagement-to-address-local-civil-unrest/ To have a community conversation on preventing hate in your community go to: https://www.niot.org/ To find a Community Mediation Center Near You: https://www.nafcm.org/ To engage in conversation across the political divide: https://braverangels.org/ To help Congress fulfill its Constitutional role: Rebuild Congress Initiative https://www.rebuildcongress.org
Clarendon Connection with Pastor Rohan Cameron. Visiting the past, Living in the present, Heading for the future spiritually. The parish of Clarendon is located in the center of Jamaica with Bull Head Mountain as the focal point. Call in to chat 661-467-2407
Photo: CAPE CANAVERAL, Fla. -- The Space Exploration Technologies, or SpaceX, Falcon 9 rocket is in position for a wet dress rehearsal at Space Launch Complex 40 at Cape Canaveral Air Force Station in Florida. During the rehearsal, the rocket will be fully fueled and launch controllers will perform a countdown demonstration. The rehearsal is in preparation for the company's first Commercial Resupply Services, or CRS, mission to the International Space Station aboard the Dragon capsule. . CBS Eye on the World with John Batchelor CBS Audio Network @Batchelorshow Scrambling commercial space booster builders. Bob Zimmerman, BehindtheBlack.com https://behindtheblack.com/behind-the-black/points-of-information/relativity-signs-deal-to-expand-rocket-facility/
This week we have the honor of having Haley Harrison on the podcast for a segment of People of Science. I met Haley at the CRS-19 NASA Social where we witnessed a Falcon 9 launch supplies to the International Space Station and toured the NASA Facilities like the VAB And Veggie Lab. Haley shares her path in STEM in pursuing her PhD in Nanoscience (which we can officially congratulate her for achieving recently! Way to go Haley!). She shares her experience finding a great team to support her through Grad school and shares advice on how to make the most of it while you are there. We also brainstorm about how nanoscience can change the future, and specifically some applications in the space industry on how things like nanotubes (carbon or boron nitride) can help us achieve amazing things! Want some quick context on Nanoscience if you're new to the topic? Check out these links: https://www.nano.gov/timeline https://www.energy.gov/science/doe-explainsnanoscience Follow us on social: - @todayinspacepod on instragram & twitter - @todayinspace on TikTok - /TodayInSpacePodcast on Facebook How to Support the podcast: Buy a 3D printed gift from our shop ag3dprinting.etsy.com Donate at todayinspace.net Share the podcast with friends & family!
Dr. Mitul Gandhi, medical oncologist-hematologist at Virginia Cancer Specialists of the US Oncology Network, highlights therapeutic advances in multiple myeloma featured at the 2021 ASCO Annual Meeting. Transcript: ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Mitul Gandhi, a medical oncologist specializing in hematologic malignancies at Virginia Cancer Specialists, which is part of the US Oncology Network. Dr. Gandhi will discuss therapeutic advances in multiple myeloma featured at the 2021 ASCO Annual Meeting. He reports no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Gandhi, welcome to the ASCO Daily News podcast. Dr. Mitul Gandhi: Thank you for having me. ASCO Daily News: Let's first look at the OPTIMUM MUKnine trial. It's Abstract 8001. And it reported high overall response rates in patients with ultra high-risk multiple myeloma with Dara-CVRd induction therapy. What are your takeaways from this study, Dr. Gandhi? Dr. Mitul Gandhi: Sure. So, the OPTIMUM study was conducted by the UK group, and it's noteworthy for several reasons. The way they had constructed the trial, they designed and developed a platform primarily to enrich for a predefined subset of very high-risk individuals, whether it was through a set of genetic assessment or with central gene expression profiling. And the way the trial was conducted, while patients were waiting to ascertain the results of the gene expression profiling (GEP) they could receive two cycles of bridging therapy. Once those results were furnished or they met the cytogenetic risk criteria, patients who subsequently consented to the intervention protocol which was a dose intensified regimen, five drug regimen, incorporating daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone. So, patients would receive induction for up to six cycles, and that would include the two cycles of potential bridging therapy as GEP was being evaluated on an every 21 day basis. And then this was followed by a modified conditioning regimen consisting of high-dose melphalan at 200 milligrams per meter squared along with weekly bortezomib which was continued even following autologous stem cell rescue, really until count recovery. Subsequently, patients received an additional six cycles of daratumumab, bortezomib, revlimid, or lenalidomide followed by 12 cycles of daratumumab and rituximab until progression. This was a complex study design with an intensified induction consolidation and maintenance phase, but it did yield a impressively high OR rate, or overall response rate, at 94% with very good partial response or greater seen in 77% after assessment following autologous transplantation, including 46% complete response (CR). And of those with CR, they had identified 63% achieving MRD negativity as well. And I think the authors should be commended for one, enriching a high-risk subset of patients both on conventional cytogenetics and/or GDP, and then two, utilizing the most active agents that we currently have to elicit high responses and then to consolidate on those following transplant. I think some of the take homes from the study are the ability to demonstrate feasibility of central genomic risk stratification related to more precisely identify and select high-risk patients as this is kind of an area of unmet need of where to augment therapy appropriately. I think it's still a question whether or not this is the exact dose intensified regimen that's going to elicit the best long-term outcomes in these highest risk patients and whether or not the conventional surrogates for a long-term progression-free survival (PFS) benefits such as MRD really apply to this as there is some controversy regarding that. Nonetheless, I think this offers a kind of a reproducible platform that can be emulated to identify the highest risk patients. You can do that prospectively, and then to selectively incorporate the most active agents and potentially the next generation of novel agents, including immunomodulators, cellular therapy, bi-specific antibodies earlier in the treatment course, and really try to elicit the deepest initial response and hopefully see that translate into longer term durable control. So, this was a complex study design that was impressively executed, and again with an ability to enrich for the highest risk subsets. ASCO Daily News: Excellent. Thanks for sharing your takeaways from the OPTIMUM trial. Well let's focus on the phase II CARTITUDE-2 study. That's Abstract 8013. This study reported that deep and early responses were yielded with a single infusion of cilta-cel in patients who had received one to three prior lines of therapy for multiple myeloma. What are your thoughts on this trial? Dr. Mitul Gandhi: So, Dr. Usmani presented the CARTITUDE-2 update on behalf of his co-collaborators. And the listeners probably are aware of some of the preliminary data that was presented at ASH as well in 2020, but this is a phase I/II protocol. Currently the phase II data are being presented with a proprietary CAR T platform which has two BCMA single domain antibodies on the CAR T construct along with a co-stimulator domain. And as kind of summarized in the title, the single dose was infused. So, amongst 113 patients who were initially recruited, 97 ultimately were treated with some fallout attributed to progressive disease. Like many of the other CAR T studies, this was a uniformly high-risk and heavily pretreated population. Median age was 61. High-risk cytogenetics were in 23% of patients. And there was about 20% of patients who had harbored plasma cytomas as well. Response rates were impressively high at almost 98%, and 67% obtaining a stringent complete response (CR). Much like the other CAR T experience, response continued to deepen over time. And encouragingly, duration of response was actually not reached time of presentation. Kind of amplifying the depth of response, of the patients assessable for MRD, 93% had achieved an MRD negative state at a sensitivity of 10 to the minus fifth cells, leading to a 12-month PFS of 77% and an OS of 89%. So, these are all welcome numbers and response data, again, in a heavily pretreated population who have been exposed to what we believe all the more active agents in the disease. In parallel with kind of response, with particularly with CAR T is the toxicity data. And encouragingly, while CRS, or cytokine release syndrome, which is typified in CAR T therapy was seen in about 95% of patients, only 4% had grade 3 to 4 CRS. So, on the whole, quite manageable. Median time to onset was 7 days with duration of 4 days and resolved with appropriate medical therapy, including tocilizumab. They did report one patient who had grade 5 CRS with hemophagocytic lymphohistiocytosis (HLH) with the remainder, I was summarizing kind of the low level of grade 3, 4 experience. There was additionally neurotoxicity and 21%, with 10% having grade 3 or higher. Again, resolved with supportive care measures. So, in totality this builds on the CAR T experience with high response rates, deep response, rates including achievement of stringent CR and high rates of MRD negativity with only a single dose of CAR T cells infused, again amplifying the efficacy of this platform on a heavily pretreated population and potentially allowing for extended treatment-free intervals as well or options for retreating in people who don't achieve MRD with a manageable toxicity profile at experienced centers. Certainly there's still work that's going to be done to better delineate the extent of CRS and how to appropriately treat that along with the neurotoxicity, but along with several other abstracts presented at this meeting and meetings prior, builds on the CAR T experience, knowledge rapidly coming to the forefront in myeloma therapy. ASCO Daily News: Great. So, some good developments for previously treated patients. Well, now I'd like to focus on newly diagnosed multiple myeloma. Let's look at the CARDAMON trial, Abstract 8000, and the FORTE trial, Abstract 8002. These studies explored novel therapies that are emerging for newly diagnosed multiple myeloma. So in their presentations, these trial investigators seem to question the value of standard of care autologous stem cell transplant (ASCT). So do you think these new data call into question the advantages of the up front ASCT approach in newly diagnosed multiple myeloma? Dr. Mitul Gandhi: That's a great question. And as providers in the myeloma community know, there's still an ongoing debate whether or not to ubiquitously apply a high dose melphalan conditioning and stem cell rescue across the spectrum of all patients with myeloma who are transplant eligible or reserving it for certain patients or not. Some of this is borne out of saving unnecessarily aggressive therapy, who would otherwise achieve an excellent response of induction. Along with some concern for secondary genotoxic effects imparted by the melphalan itself and perhaps propagating more biologically aggressive subclones. And to that end, these two abstracts explored whether or not transplant-free approaches would be feasible. So, the CARDAMON study enrolled 281 patients where all patients received kyprolis, cyclophosphamide, and dexamethasone for four cycles, and of those patients achieving at least a partial response (PR), they were subsequently randomly assigned to continuous KCd or autologous stem cell transplant. And what the authors concluded, KCd induction followed by KCd maintenance was not inferior to autologous stem cell transplant with PFS at 2 years measured at 70% versus 76%, and that difference meeting the criteria that was prespecified in terms of their confidence interval for noninferiority. So, on the surface you could argue based on the results that were presented that there was equivalence. But a few caveats that are important to bring up, the first was that follow-up was short. It was only two years, and so it's very plausible that with longer follow up, the noninferiority that was seen may not be borne out with extended follow up. The other point the author's note was that MRD negativity was higher in the autologous stem cell group at 53% compared to 35.8% of the non-transplant group. And various studies have reported this to be a reasonable surrogate for long-term PFS, not always. And so again highlights the fact that with longer follow up, we may see a separation of the curves. Their subset analyses did not demonstrate any obvious areas, rather a subset of patients that would have derived preferential benefit, although the numbers were quite small. So, while an initial conclusion may be that there was a relative equivalence for a transplant-free approach, I'd argue that it's probably still a bit premature to make that conclusion and noninferiority may not be identical with longer follow up. And additionally, this probably is an induction regimen that is not as commonly employed in the U.S. But it does again help to the body of literature regarding this question of transplant for all versus not, although there may be hopefully more discriminatory power to see where it would be beneficial. The FORTE study presented by Dr. Gay and her colleagues was a bit larger at 464 patients and slightly different. Patients were randomly assigned to one of three arms, carfilzomib plus cyclophosphamide plus dexamethasone for four cycles induction followed by autologous stem cell rescue, carfilzomib, lenalidomide, dexamethasone induction for four cell cycles followed by autologous stem cell rescue, or carfilzomib, lenalidomide, dexamethasone without autologous stem cell for 12 cycles. So, those were the three arms, and then there was a second randomization to lenalidomide versus lenalidomide plus carfilzomib maintenance. Patients were prespecified in terms of their cohorts of high-risk, standard risk, or the so-called double hit which was people, patients rather, harboring two high-risk cytogenetic features. And so what the authors concluded that across the board, the arm containing carfilzomib, lenalidomide, dexamethasone with autologous stem cell rescue demonstrated superior PFS compared to all of the other, rather, the other two arms. And similarly intensification of maintenance incorporating kyprolis plus revlimid resulted in superior 3 year PFS compared to revlimid alone in 90% versus 73%. So what do we take away from this? Well, it's not a conventional induction approach in the U.S., with RVd still predominantly being used, particularly after the endurance data was presented at last year's ASCO showing equivalence of a bortezomib induction strategy versus carfilzomib strategy. It does support and lend credence to the use of high dose melphalan autologous stem cell rescue as patients who are in this arm seem to enjoy a more longer and durable progression-free survival across all subsets, including standard risk, high-risk, and the double hit strategy. So there wasn't any particular subset that could be identified that would have performed equally well with KRd alone without autologous stem cell rescue. Putting these two abstracts together, I would still argue that there remains a very important role for our high dose melphalan and autologous stem cell rescue currently an induction, rather following induction, in appropriately selected patients. And while we may not have identified patients on preselected criteria based on their cytogenetic risk, it's conceivable that we might identify response based criteria, whether it's MRD or otherwise, to perhaps see who may be able to abstain from transplantation. And there are several protocols that are actively accruing, some that have been preliminarily presented, and some that will be presented in subsequent meetings that might lend evidence to this. But for now based on the data sets that were presented at this year's meeting at ASCO, there still seems to be support for use of high dose melphalan and autologous stem cell rescue. ASCO Daily News: Right. Well staying with the issue of transplantation, for over a decade investigators have been exploring the curative ability of alloHCT in select patients with high-risk multiple myeloma. Fast forward to 2021 and the phase II double blind, placebo controlled, blood and marrow transplant clinical trials network 1302 trial. That's Abstract 7003. This study found that when performed with a reduced intensity conditioning regimen of bortezomib, fludarabine, and melphalan, alloHCT was safe in patients with high-risk multiple myeloma. What are your thoughts on this, and do you anticipate further research on the role of alloHCT in patients with multiple myeloma and high-risk features? Dr. Mitul Gandhi: So, this is an interesting abstract presented by Dr. Nishihori and her colleagues specifically looking at the role of ixazomib maintenance following a reduced intensity conditioning regimen of fludarabine, melphalan, and bortezomib in patients with high-risk myeloma. So this study was a phase II study enrolling patients under the age of 70 with high-risk myeloma defined by cytogenetics, or presence of plasma cell leukemia, or relapse within 24 months of an autologous stem cell transplant, which has been identified as a prognostic factor independent of baseline risk of poor outcomes, with the goal of administering the reduced intensity conditioning followed by HLA matched donor unmanipulated graft with methotrexate and tacrolimus GVHD prophylaxis, and starting at day 60, randomization ixazomib versus placebo maintenance. It should be noted that the goal initially was to enroll 110 patients, but ultimately only 57 patients were accrued over the course of 4 years from 2015 to 2018, 52 ultimately receiving an allogeneic HCT and 43 proceeding to maintenance. And so this in and of itself highlights the challenges of running an alginate transplant trial in myeloma mainly because sick patients may be by the point where allogeneic transplant is being entertained or inability to achieve sufficient disease control in order to pursue the transplant. But with respect to the study itself, they reported a PFS and overall survival (OS) outcome at 24 months, of 52% and 85% respectively, with transplant-related mortality at a respectable 11%. So in context of the small studies that had previously been reported in this space of allo SCT and myeloma, this was improved treatment-related mortality related to the procedure itself. With respect to the question at hand regarding the role of ixazomib maintenance, interestingly they showed no difference in PFS, with ixazomib versus placebo at 55% and 59% and OS at 95% and 87%. In terms of the toxicity, it was not trivial. Grade 3 to 4 acute GVHD at day 100 was 9.5% in the ixazomib arm, 0% in the placebo arm. And chronic GVHD was 69% versus 64%. So, where do we take all of this data in context? I think there is a signal of lower transplant-related mortality compared to historical controls, and so it probably speaks to the improved ability to identify patients and also get them through transplant with this modified conditioning. The follow up, however, was abbreviated, and so there may be increased relapse over time as well. In terms of where does this fit in the armamentarium of therapy with refractory myeloma, I think that's still to be determined. And perhaps it's going to be occupying more of a niche role given the blossoming repertoire of highly efficacious immune-based agents, whether it's modified cellular therapy with CAR T a upcoming NK cell products that are being explored, and of course by specifically antibodies that have been robustly presented at this meeting demonstrating impressive responses. So, it's very conceivable that patients who were previously would be entertained for allogeneic SCT will now be in are treated with this kind of repertoire of novel immune agents. And so it may become a more of a niche role in patients who have exhausted all conventional or investigational approaches, but it does suggest that with this modified reduced intensity conditioning, treatment-related mortality can be lowered. With respect to the question at hand, it does not appear as though maintenance ixazomib helps these patients. And so observation alone following transplant versus an alternative maintenance strategy would be indicated. ASCO Daily News: OK. Well I'd like to ask you about the Apollo trial. That's Abstract 8046. This study looked at health-related quality of life of previously treated patients with multiple myeloma on a regimen of pomalidomide and dexamethasone plus subcutaneous daratumumab. Any surprises here, Dr. Gandhi? Dr. Mitul Gandhi: So, the Apollo study is a phase III trial primarily evaluating the efficacy of pomalidomide plus dexamethasone versus pomalidomide dexamethasone plus the incorporation of subcutaneous daratumumab in patients with myeloma who had received one prior line of therapy. And primary outcomes data had already been presented with improved rates of disease control with incorporation of daratumumab. With respect to this abstract, Dr. Terpos presented quality of life and patient-reported outcomes that was collected in parallel with the intervention arm of this study, and so they utilized the EORTC 30 item questionnaire to assess quality of life and subjective data from patients. And what they found was in the patients who had been on the DPD arm, or the daratumumab arm, there was a greater reduction in pain and no real augmentation or introduction of increased adverse events related to the additional agent. Moreover, there was no decline in physical or emotional functioning with DPD, but there was worsening decline in those elements compared to baseline for patients receiving pomalidomide and dexamethasone alone. There were higher rates of improvement with respect to control of disease symptoms, physical functioning, emotional functioning on the DPD arm. So, what does this tell us? Well in general, I think we've seen a plethora of agents that have improved outcomes with our patients with myeloma who are now living for years on therapy, increasingly and often even into a second decade. And so gaging the impact of therapy on quality of life, subjective sense of well-being is critical as these patients are going to be on therapy for quite a while. And so independent of serologic and laboratory response, we certainly want the interventions to improve functional capacity. And this data would suggest that you can achieve that in parallel with achieving better and deeper responses, which intuitively makes some sense, and they are often congruous. Involving the incorporation of an additional agent didn't worsen the sense of adverse events, but in fact improved the general sense of well-being. So this adds to the body of work of daratumumab on a MM dexamethasone backbone parting benefit without toxicity and also lending credence to the notion that by improving myeloma parameters, we're going to be in parallel improving quality of life. And so with the advent of all the other agents and novel compounds that are being developed after the acute toxicity period, we'd also expect to see improvement in quality of life as well. And so I think this was an important contributor to telling us this. ASCO Daily News: Excellent. Well thank you so much, Dr. Gandhi. I really appreciate your time today. Before we wrap up, any final thoughts from you on advances in multiple myeloma? There's certainly some really impactful work being done in the field. Dr. Mitul Gandhi: Yeah. I think I would encourage all the listeners to review the abstracts presented, particularly the oral abstracts as they get into some of the granularity on detail regarding the individual CAR T and bispecific antibody products, and very nicely demonstrate the durable responses that are being achieved in heavily pre-treated patients. Obviously kind of the next sort of hurdle in the field is to democratize these agents and make sure they're readily available for all patients. And there's a lot of work being done to ensure that management of the acute toxicity can be managed more broadly. So I think I'd pay particular attention to the oral abstract sessions which really demonstrate the novel agents that are being investigated. ASCO Daily News: Dr. Gandhi, thanks again for being on the podcast today to highlight some great new therapies in multiple myeloma. Dr. Mitul Gandhi: Thank you for having me. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts. Disclosures: Dr. Mitul Gandhi: None disclosed. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Today, we're joined by Fionn (aka PotatoPlunderer) to hang out and talk about some of our tips on creating homebrew content! This one is a ton of fun, so come along with us! Question(s) discussed: 1. You're creating a homebrew campaign. Where do you start the process and what follows after? 2. How do you best balance homebrew mechanics? For that matter, what are your opinions on homebrew in general? 3. How do you determine CRs for homebrewed monsters? 4. What are your tips on creating homebrew classes/races/backgrounds/etc.? Dragon's Hoard Item: Crown of the Library of Leng Contact us: InterPartyConflict@Gmail.com Visit our blog: www.interpartyconflict.com Find us on Twitter: www.twitter.com/InPartyConflict Or on Facebook: www.facebook.com/InterPartyConflict/ And join our Discord: http://bit.ly/interpartydiscord
Originally from Cambridge, England, Ellie is a Maryland transplant since 1997. She proudly helps her clients buy and sell all types of homes in Howard County, Carroll County, Anne Arundel County, Baltimore County & Baltimore City. Every transaction is different and everyone has different needs. Ellie caters to those needs and establish lifelong relationships. Ellie has been licensed for 19 years, and is luxury certified in CLHMS, MRP, CRS, MREA. She uses modern technology and multiple resources that other agents do not use. As a full-time agent her number one goal is to provide exceptional service ALWAYS. In today's episode, We discuss creating a strong community presence and integration using social media. In this episode, you'll learn... Becoming the digital Mayor Creating a community Facebook page Interacting with individuals in your locality Giving publicity for local businesses Hosting events Links and resources mentioned in this episode. https://www.facebook.com/LivingInTheVille/ https://epikhomegroup.kw.com/ To subscribe and rate & review visit one of the platforms below: Follow Real Estate Success Rocks on:
Justin Timberlake – “Suit & Tie” (DJ Meme Tuxedo Mix) [-] Ed Sheeran – “Shape Of You” (Andrea Fiorino Forget Me Booty) [-] The Whispers – “And The Beat Goes On” (SanFranDisko’s Old School Chop Up) [-] Bruno Mars – “24K Magic” (Discotron Remix) [-] Squirt D & CRS – “Holiday” (Samma Lone Remix) [Skeet […] The post Andrea Fiorino Mastermix 12th May 2021 appeared first on SSRadio.
Today's episode focuses on two major victories that many on our side have maybe been afraid of cheering on -- first, the agreement between Chuck Schumer and Mitch McConnell on a power-sharing arrangement that will enable legislation to come out of equally-divided Senate committees, and second, the impeachment vote of 55-45 that the Senate has jurisdiction over Trump's impeachment. We'll tell you why these are real victories worth celebrating and break down some Senate Rules while we're at it! Then, we have an inspiring interview with Ruben Amaya, a 19-year-old running for the Maryland House of Delegates. Links Yes, we're aware of the Latinos for Trump lawsuit; it's crazy and hilarious and we'll be covering it in some way, we promise! On the Senate rules: (a) go read Rules XXV, XXVI 7(a)(3), or any other rule for yourself; (b) check out the 2001 plan (S.R. 8); and then (c) read this CRS report explaining "filling up the amendment tree." On impeachment, you'll want to read Brian Kalt's seminal 2001 Law Review article. Finally, if you'd like to check out Ruben Amaya's campaign, head on over to his website at rubenamaya.org! Appearances None, have us on! -Support us on Patreon at: patreon.com/law -Subscribe to the YouTube Channel and share our videos! -Follow us on Twitter: @Openargs -Facebook: https://www.facebook.com/openargs/, and don’t forget the OA Facebook Community! -For show-related questions, check out the Opening Arguments Wiki, which now has its own Twitter feed! @oawiki -And finally, remember that you can email us at email@example.com!