Podcasts about Median

Median home pricing at $400,000? We need answers! So we talked to Andy Babula who is a professor of Real Estate and Finance with the Opus College of Business at the University of St. Thomas about why the housing market is so high - in fact the first time it has hit $400,000 ever! Then we discuss the latest addition to your Minnesota Twins uniforms! Also, in DeRush Hour News Headlines we honor the closing of Edina Grill after three decades, high paying jobs where you can make a haul of cash and much more!

A new track by DJ Habett from the album "Nach Mitternacht" (2025-07-14). Tags: Dub, Beats, Unity, Junction, Median, Operator, Fuses, Future, Peace CC(by). Production notes: Laidback surface of a dub before a solid day off groove. Difficult mastering. Better after pushing.

Podle agentury Median u nás letos klesl historicky na nejnižší úroveň zájem o volby. Ještě před dvěma lety chtělo jít k volbám skoro 80 procent dotázaných. Počátkem letošního roku jenom něco málo přes 60 procent, v dubnu 54, v květnu už jen 53 procent. Trend je zřetelně klesající.

Podle agentury Median u nás letos klesl historicky na nejnižší úroveň zájem o volby. Ještě před dvěma lety chtělo jít k volbám skoro 80 procent dotázaných. Počátkem letošního roku jenom něco málo přes 60 procent, v dubnu 54, v květnu už jen 53 procent. Trend je zřetelně klesající.Všechny díly podcastu Názory a argumenty můžete pohodlně poslouchat v mobilní aplikaci mujRozhlas pro Android a iOS nebo na webu mujRozhlas.cz.

Die Themen im heutigen Versicherungsfunk Update sind: Jeder fünfte Versicherungsvertrag wird online abgeschlossen Laut aktueller GDV-Auswertung wurden 2024 rund 22 % der Versicherungsverträge digital abgeschlossen – etwa über Websites, Vergleichsportale oder Apps. Besonders hoch ist der Digitalanteil bei Kfz-Versicherungen (29 %) sowie bei Krankenzusatz- und Auslandsreiseversicherungen (über 27 %). Trotzdem bleibt persönliche Beratung zentral: Rund 80 % der Verträge kommen weiterhin mit persönlicher Unterstützung zustande, insbesondere bei Lebens- und Krankenvollversicherungen. FinTechs fordern Tempo bei Altersvorsorge-Reform Mehr als 30 digitale Finanzunternehmen – darunter N26, Scalable Capital, BlackRock und growney – appellieren an die Politik, die private Altersvorsorge zügig zu reformieren. Gefordert wird eine Kombination aus Frühstart-Rente für Kinder und einem flexiblen Altersvorsorgedepot ohne Garantien. Ziel sei es, Kapitalmärkte besser für den Vermögensaufbau zu nutzen. Der gemeinsame Appell unterstreicht die Dringlichkeit und das Potenzial einer kapitalmarktbasierten Vorsorge in Deutschland. Datenmangel begünstigt Fehlentscheidungen 60 % der befragten Finanzentscheider in Deutschland haben 2024 mindestens eine geschäftliche Fehlentscheidung getroffen – meist ausgelöst durch externe Faktoren, falsche Markteinschätzungen oder unzureichende Datenlage. Das zeigt eine aktuelle Coface-Umfrage unter 204 CFOs. Zwar greifen 82 % inzwischen auf deutlich mehr Daten zurück als vor fünf Jahren, dennoch bleibt der Bedarf an zuverlässigen Wirtschaftsauskünften hoch. Besonders wichtig: Aktualität und Verlässlichkeit. Hypoport InsurTech holt Markus Niederreiner als CEO der Smart InsurTech AG Die Hypoport InsurTech AG verstärkt sich: Ab dem 15. September 2025 wird Markus Niederreiner neuer Vorstand der Hypoport InsurTech AG und übernimmt zugleich die Geschäftsführung der Smart InsurTech AG. Zuvor war Niederreiner CEO von Hiscox Deutschland. Mit der Personalie will Hypoport die nächste Wachstumsphase und die Weiterentwicklung des eigenen B2B-Marktplatzes einleiten. Cyberrisiken unterschätzt: KMU investieren kaum in Schutz Laut einer Studie von Coalition haben 83 % der kleinen Unternehmen in Deutschland in den letzten fünf Jahren einen Cyberangriff erlebt – dennoch widmet mehr als die Hälfte von ihnen der Cybersicherheit weniger als zehn Stunden pro Woche. Die Diskrepanz zwischen Risikobewusstsein und tatsächlicher Absicherung ist groß, warnt Coalition-Manager Martin Swider. Jeder zweite Haushalt besitzt über 100.000 EUR Vermögen Das Medianvermögen deutscher Haushalte lag 2023 bei 103.100 EUR – das zeigt eine neue Studie des Instituts der deutschen Wirtschaft (IW). Besonders hohe Vermögen finden sich bei 55- bis 64-Jährigen (Median: 241.100 EUR). Laut IW-Experte Maximilian Stockhausen sollte die Politik stärker auf Entlastungen beim Arbeitseinkommen setzen, um Vermögensbildung zu erleichtern.

Cáel  Defeats The Illuminati: Part 19The Great Hunt.Book 3 in 19 parts, By FinalStand. Listen to the ► Podcast at Explicit Novels.‘The Hunt is never an easy thing because in the Wild there are things which hunt the hunters'September 11th: First Day Of The Great HuntCentral ArgentinaFelix was still nursing his hurt hand when I came back from my Ishara-space."Well?" he smirked."Plenty of good news," I smirked right back from the place where I had dropped when Felix had cold-cocked me. "Suffice it to say the weather on the final day will be in our favor ~ no more precise answer than that from the goddess SzélAnya ~ plus our horses will not throw us, or give away our position. That's from the Goddess Epona by the way.""Finally, the Goddess Ishara will be watching over us and our travails... she will send omens to warn us of hunters closing in as well as talk to me in my dreams. Apparently she doesn't want me; us; to shame her in this contest so is taking this competition seriously. Mind you, this means the other goddesses will be taking this contest seriously as well, so we have our work cut out for us again.""What is Ishara the Goddess of again?" the teased me."Oaths, love and medicine," I repeated my answer."Fine," the grinned, "is there any goddess in my corner?""None that bothered talking to me," I snorted. "Want me to knock you out and see what you can see?""Nah... I'm Felix Melena. I work better alone.""You mean in alone in a team of two, right?""Yeah; a team of four actually, Nyilas. Don't forget our mounts," Felix motioned to our two horses.I was ecstatic because they had brought Peppermint down from 'Summer Camp' for this romp through the Pampas. To me she was the perfect mare for this endeavor.Felix had been gifted with a spirited gelding named 'Thunderbolt'; 'Rayo' in Spanish. He was a black haired beast with white sox and a white diamond on his forehead. Felix had wanted a stallion, but the Horse-mistresses of Epona had nixed that choice as highly impractical for a horse-virgin such as himself. I had to agree as stallions had far too much spirit and the likelihood of one making noise when it smelled an unknown mare was far too high... so a gelding it was.Not that an 'unknown' mare was that much of a possibility. See, we had been put down where the other thirty huntresses would also be starting from; a makeshift corral our host Freehold had put together as the entrance to some 'badlands' in which the hunt would be taking place. There ten Amazons; with their own mounts; manned the place, fed the horses and made sure no one cheated out of the starting gate.We had our 24 hours head start on our pursuers, but that didn't turn out to be the huge edge we thought it would be. We were given the first part of our map... which led to the area we would find our second part of our map... and so on until sometime late Saturday night, or Sunday morning, we would find the final part of our map which would direct us to where our extraction point would be.We were to be extracted at Noon; not sunset as we had originally been told; on Sunday. Actually, anytime between ten minutes before to ten minutes after... so fair this was not seeing as we were novice outdoorsmen. Still, those were the rules we were given so off we went early Thursday morning. In the truest Amazon fashion, this was to be a contest which required the utmost skill and endurance to win.Heading out, Felix and I were deciding on what the enemy strategy, or strategies, would be. We figured some would start by simply trailing us seeing as how they were better both at tracking as well as doing so from horseback. The second group would follow a different, but equally difficult 'Treasure Hunt' toward our final point of extraction and wait for us there.I reminded Felix that neither he nor I nor any of the Amazons would be riding our horses to death, or even injury, because that wasn't the Amazon way. Such callous disregard for one's mount wasn't in them and we had to follow that dictum, or suffer irreparable harm to our own 'honor' should we do so and somehow win. Doing so and losing... we decided to not even go there.This also meant we had to take time for our horses to graze and find water for them to drink along the way. After getting that lecture, Felix wondered out loud if it wouldn't be a better idea for us to let our horses loose and 'hoofing' it ourselves seeing as how the Amazons would also have to follow the same horse etiquette. I had to remind him reluctantly how much faster horses could travel. Horses were the way to go.The difference was there was no rapid charging across the landscape with the Sun at our backs as we headed out. No, we took it at a steady trot until we hit our first terrain feature; a steady gradient cut in the side of a canyon which had been created over the millennia by the forces of wind and rain. Down we went. Our horizon sunk down until all we had were the walls of the canyon.Our map directed us to take this route to the first 'treasure horde', whatever that was. By the way we were moving and how the Sun slowly crawled up above us; recall it was almost 'spring' down under; we figure we were making good progress toward our first target... which we located without too much hassle around noon.It was a Bonanza! Not for us, but for the horses. We had four bags of grain for our mounts. We humans received some sort of indescribable jerky (since it was probably not human we decided to eat it... later [it turned out to be the local flightless bird and it tasted like chicken jerk jerky too!]). There was also the second part of our map which led us farther out into the wilderness. Off we went.Third Treasure Trove.By evening we had found our third treasure trove. The second had contained two compasses and two hatchets (Yippee!). The third had contained two sections of twenty-five meter rope and some flint and tinder so we could start a fire. Felix was all for this as it was butt-numbing cold already and we were damn tired from a day full of riding.We compromised by creating a banked fire. We also decided to sleep instead of pushing on. It was pretty dark outside even with the three-quarters Moon above. We definitely didn't want to walk our mounts into something which could bring them up lame this early in the contest. I assured Felix we couldn't abandon them and leading them would be torture. Essentially we would be disqualified.I won the compass toss and got to sleep the first part of the night. Felix woke me around Moon-set and then I kept watch; there were predators about, or so we believed; until sunrise. Then we ate the last of the jerky, fed and watered our mounts then head out once more. This time our hearts began to hammer within their cages and every noise had sinister implications.See, the Amazons are cheating bitches of all cheating bitches and could have started after us at 12:01 last night and pushed on following our trail through the night. Being expert horsewomen and spectacular trackers they could do shit like that. We, their prey, had to be clever in other ways. What those ways were weren't relatively apparent though.Maybe Pamela could show up and, after slapping me upside my head, give me a clue. No Pamela arrived though so we were on our own. Shortly after the Sun crested the canyon walls; we kept to the canyons just in case; we came across the fourth 'trove'... and it was chilling. We received two binoculars and some more jerky (it was to be our lunch). The binoculars were the chilling part because if WE had some then most likely the Amazons behind us had some as well.Also, the way from our fourth treasure to out fifth put us in the horns of a dilemma. We could either cut over the sides of the canyon to where the fifth treasure trove/map was, or keep to the canyon and travel three times the distance. After a quick discussion followed by some 'rock-paper-scissors' (complete with a prayer to Dot Ishara), I won, so up and over the side we went.To reduce the size of our silhouette, we dismounted and led our horses across the... and stumbled across a herd of cattle; Sweet Mother Ishara! We moved through the herd, waved to the accompanying Amazon gaucho, and went on our way. Felix muttered something about my 'dumb' luck. He-he-he-he-he... We talked to the gaucho, turned on the charm and convinced her to not tell any of our pursuers we had come by this way.She was like nineteen years old and I could tell really took a shine to Felix... so he promised to come back and visit her the moment he won the contest. After we departed her and her track-erasing herd of cattle, I pulled him aside."You had better keep that promise to that girl. If you don't, she and her kinfolk will hunt your ass down and tag you like a mule deer in the Yellowstone," I cautioned him."I know. I know," he grinned. "These are some crazy ass bitches. Besides, being the lone male in a freehold of women has its own appeal."I thought we were in safe territory again when Felix finally asked that doom-laden question."Cáel , where have all their dudes gotten off to?"'Oh shit', I mused. How much of the truth could Felix handle?"I'm only telling you this because I like you," I said then took a deep breath. "They sold them to the Nine Clans... they are a bunch of assassins.""Really?" he studied me. Like he was going to catch me in a lie after four years of dating the most dangerous game on this Earth; girlfriends."Really. Where do you think they get those legion of ninja and combat fighters from? Sure their life expectancy isn't what we have, but it is much better than they would have if they stayed home." There was some part of the truth in that."That seems... short-sighted.""What do you think guys like us are for? Now they won't have to kidnap local passer-byers for weeklong orgies.""How come words has never gotten out about this?" Felix was relentless."It has from time to time, but Havenstone makes sure such reports are relegated to the realm of tabloids and UFO aficionados. If that doesn't work, they bribe some people to bury the story. If that doesn't work, they kill some people.""Now that I believe," Felix nodded."That they kill people to keep their secrets?""Absolutely. They look like the kind of girlfriend who wouldn't be happy unless she burns your balls before your eyes after you break up.""How succinct," I nodded back."So, are we ever going to see Khalid, Trent, or Brian again?""Sure... they are only being kept prisoners and milked of their seeds... but I can arrange for you go to go meet them if you really want to," I offered."No thanks," Felix shook his head then grinned. "They washed out while only you and I remain. Let me find them on my own and get some sort of permission from Ms. Love (Katrina) first. I thought Khalid was kind of cool and Trent was the kind of brother I could invite out for a beer, or ten.""Not Brian?""Brian was too invested in himself and his weevil-ing ways. I couldn't trust him at my back, or with my girl. Mind you, I wouldn't trust you with my girl either, but we are otherwise okay.""Smart move. I have exceedingly low impulse control around the ladies plus an over-developed libido.""Yeah," he smiled my way. "I'd trust you in a knife fight, but not with someone I loved. You are way too smooth, Nyilas. Way too smooth.""What brought that revelation on?""Ms. Lee (Brooke). Normally I can mend any fence with any girl I come across, but not with her after she'd been with you. I admire that," he studied me."So, are you and Gene going to be a regular thing?""Yeah. I think so. I still expect me to be getting plenty of tail at Havenstone once I win this thing, but having a less-lethal girl on the outside wouldn't suck either."So much like me... I admired that about the guy."Once we win, don't ya mean?""Sure thing, Nyilas," he chuckled. "I figure it helps me to help you across the finish line. The better standing you end up in the better an ally you make back at work.""That reminds me; Katrina told me they are going to spin this; your participation in this inaugural Great Hunt is that all sins are forgiven; yadda, yadda, yadda. Thus you still walking around Havenstone being the bad boy you are.""Clever lady and always thinking ahead. Is she seeing anybody?""No, and dude, you don't want to go there. She is far too clever by half to fall for any of our reindeer games. She scares me," I cautioned him."All the more reason to pursue her," he snorted."Go for it," I shrugged. Hey, I'd warned the guy."What about that blonde number I saw you with... Elsa was it?"Oh, he knew exactly who Elsa was, but he was acting all nonchalant about his treatment at her hands."Yeah. Elsa. What about her?""Is she in your stable?""Nope. Not really," I shrugged. "Going after her too?""Oh, definitely.""Good luck with that," I sighed. He'd learn the hard way."There is something you are not telling me.""Yeah. She has the hots for me. Wants to own me... and not in a good way.""Oh... is that your way of cautioning me to be wary of her?""Most definitely. Elsa is one scary lady and she already knows who and what we both are.""What are we?" he was eyeballing me again."Hunters on the prowl. Guys who like a challenge. In your case, the guy who only wants the best. I'm more of an omnivore.""You mean you are a man-slut," he snorted."Got me," I chuckled."So, you think she's out of my league?""No. I think she is Katrina's friend and Katrina sees right through both of us. Elsa might not have those interpersonal skills, but she's twice as lethal. Trust me on that; I've fought her.""How tough was she?""Beat me black and blue then choked me out because I wouldn't surrender.""Oh... I'd like to get her on the mats.""Good luck with that then. Become a 'Runner' and there is even more I can tell you about her. Right now it is all simply in-house stuff.""Corporate confidentiality details, eh? Executive Services purview and stuff like that. Man, I was wrong to look down on your branch of service. I apologize.""Why thank you. I honestly never thought I'd get a sincere apology from you.""I can be wrong once in your lifetime," Felix laughed, "and I'm man enough to admit it.""Oh... and thanks for the sim-cards. They helped me get off that deserted atoll.""No problem. That was Katrina's idea though.""Well, you got them to us so surreptitiously the Chinese suspected nothing.""Don't you mean those rogue Albanians?""Yeah... them too," I laughed along with him."I think we can be friends, Nyilas," he grinned."I think so too. I didn't think so originally. On the first day you and the others treated me like the country bumpkin, but now I think you see me as a survivor... just like you.""Precisely. You know I had the option of leaving Havenstone... no matter how this affair turns out.""And you didn't take it? Who offered you this opportunity anyway?""Katrina.""It might have been a ruse," I warned him. "These bitches don't play fair.""I took that into account... but I love the challenge of this place. It is like no other work environment on Earth. Challenges every day, hot women all around, and the chance to risk my life on a monthly basis. Screw regular corporate America. I've found the place where I belong."Felix sounded so enthusiastic. I hoped he understood the fate he was embracing. I also hoped he found a niche in Havenstone which allowed him to live out his life... hopefully a long, long life. Maybe I should warn him about the 'cliffs'? Perhaps once we had won and were safely back in Havenstone's motherly embrace.Hiding.Fortune favored us backtracking from our seventh treasure trove; our dinner and more grain for the horses. A few birds flew up out of the brush ahead of us. I took that as a sign from Ishara."Felix," I hissed. "Hide!"We looked around and found a draw away from the main canyon floor for us to slink into. I used some brush to cover our side tracks then ran back to cover.No sooner had I gotten there than two Amazons came trotting past us. The lead one was Svetlana Inara and she was tracking us from the saddle. The second one was Beatrice Astarte who was scanning the environment as they moved together following our trail up this vein of the canyon. As soon as they were around the next corner of the vein, Felix and I mounted up and raced down the other way.The sand floor covered our hoof-falls and we had to go that way anyway. We had barely covered the distance to the next draw when we spotted two more Amazons following our earlier trail this way. We had Two Amazon parties on our trail and it wasn't even Friday night yet! This group spotted us and gave chase. They must have ridden their horses hard to get this far because we quickly left them in our dust.This allowed us to slow down a bit and deviate over to where the eight 'treasure' was. Our map had us going back down his particular draw which I thought was most unwise, so we went over the lip of the draw dismounted and led our horses at a rapid run; for us humans; across the greater landscape. Thank SzélAnya, a late afternoon rainstorm fell upon us as we dropped down into the next vein of the canyon before the pursuing Amazons crested the draw we had exited.We walked through the rain until the sun set then debated what to do next. We were going to need light to figure out where the eighth treasure was at; they were all somewhat hidden. We had to keep moving no matter what because we doubted the Amazons on our asses were going to let up. We decided when we got close to the eighth treasure horde I would do the searching while Felix stood watch on the entrance to the draw.Using a hatchet I cut off a branch from a bush and set it alight so I could see what I was doing. It took me twenty long minutes to figure out where the treasure was hidden... night-vision goggles and the map to the ninth map piece. Gleefully, I went back down to where Felix was except... no Felix. Oh Shit! I slipped back and put on my night-vision goggles, got a hatchet at the ready and returned, scanning about.I spotted one Amazon... she was Carla Nemain... and I recalled her being teamed with Ella Mielikki. Anyway, I tried to sneak up on Carla and it almost worked. At the last moment the cloud cover cleared and the three-quarters Moon revealed me. She spun on me with twin fighting sticks while I tried to brain her with the flat side of my hatchet.Yours truly took two punishing blows to his ribs while only clipping her with my hatchet. Still, the blow appeared to cause her to stumble so I pressed my advantage. I knocked one of her two sticks out of her hand then missed twice. I thought I heard someone coming up hard behind me. Well... fuck!"What do you have?" Carla grumbled. "Are you trying to kill me?"I kept silent, pulling out my second hatchet and pressing my luck a little further. I disarmed her and then hammered her down with a hatchet to the top of her skull. Down she went. I spun around just in time to see Ella Mielikki coming at me with a lasso. She launched it a second too late and I was able to bat it aside. She drew her honor blade and kept coming though."Ella... I have two hatchets. This is not a fight you can win," I addressed her."You won't kill me," she kept advancing."Of course not. We are sisters, but I can do... this!" and I attacked her with the flat ends of my twin hatchets. I so had her too... or I would have had I had the extra moment to ensure Carla was unconscious.She wasn't. She jumped me from behind then Ella rushed in from the front and I went down in a tangle of arms, legs and torsos. I was doing surprisingly well wrestling them both despite the odds until Ella put her knife against my throat."Give up," she panted. "You have been captured. Admit it!""I surrender," I sighed then relaxed my body. My two hatchets dropped to the ground."Let's bind him up too," Carla grinned. They proceeded to tie my hands behind my back then my legs together. Then then gave each other a celebratory 'high-five'. Then came their pillaging of our loot. They especially loved our night vision goggles and the grain for 'their' horses. They abandoned our horses, put loose nooses around our necks and began riding off down the canyon, their horses feeding on the grain in feedbags... and there was a suitably humbled Felix...To do so they had to untie our legs, but they compensated for that by tying our elbows together behind our backs as well as our hands. It was a rather painful affair. All in all, our captors were quite triumphant. After a while, I decided to speak."So, how did you catch us so fast?" I asked Carla. She had my noose."I prayed to Nemain and then picked a compass point and rode that way. We came across your path and followed you here."So you weren't the group following us from the afternoon?""No... you were being followed?""Yes... by two groups... both of whom tracked us from the beginning," I sighed."Ella," Carla addressed her companion. "We had better get a move on. There are four others on our track.""Damn it," Ella grumbled. "You take both males. I'll double back and start masking our trail. You pick a different compass point and I'll catch up.""Okay. Come here," Carla accepted Felix's noose from Ella. "We are going... north by northwest."Ella doubled back and was soon out of sight. Carl took the next draw she came across and kept up a steady walking pace. As a matter of safety, she didn't wrap our tethers around her saddle horn on the off chance her horse took off. We could be dragged to death of we were attached to the horse. So, we had a momentary advantage... and took it.I spotted Felix counting down with his fingers behind his back. I spotted him at '4'. I rapidly signaled '3', he went to '2' and I finished up with '1' then we lunged backwards trying to pull her off her horse. With my luck, she tumbled down on Felix's side, horse rearing up. I ran for it, quickly pulling my noose along with me. I heard Carla and Felix cursing behind me.It was gut-check time. I could abandon Felix or attempt to double back and help him with only my legs because my hands were behind my back."Fuck it," I cursed silently as I doubled back. In the forefront of my mind was the notion Felix would come back for me if the roles were reversed. In I charged.Felix was standing, trying to use his martial arts kicks to keep her at bay.He was also absorbing the majority of her concentration because; again; she didn't notice me until I was right on top of her. I put a shoulder into her diaphragm, taking her down and knocking her knife out of her hands. Felix didn't waste a moment giving her as snap-kick to the cranium... knocking her out. I picked up the knife and backed up toward my partner.First I had to saw through his elbow bonds and then his bound hands to free him. This all took precious time. I had just freed him when Carla began moaning. Felix looked to me then to the horse."Go," I urged him on. "Go to the next site and then double back for me. You know which way they will be heading and it is you on horseback versus two of us who aren't."He gave me a quick nod of the head then jumped into the saddle... and almost spilled himself over the other side, but then was off like a flash. I ran off in the other direction. Of course with the minimal lighting and my arms tied behind my back I didn't expect to get too far, but what realistic choice did I have. I certainly wasn't going to give up, damn it.[The Politics Of Not Playing Fair]In hindsight, knowing the Amazons were cheating bitches of cheating bitches, I should have tried to cheat more, but I ended up thinking too much about the male version of honor and not enough about winning. Thankfully, others were much more invested in me winning than that. Add to this and I had family I really hadn't counted on seeing things that way.And then there was the Sanctity of the Contract to consider... which I clearly hadn't, though the opportunity to do so was right there all along.As I was fleeing for my life I caught sight of one person running past me to my right and another to my left as a third slammed into me and took me down. For an instance I was thinking 'now they are operating in groups of four!' then the clothing of the three entered my consciousness. They weren't dressed like Amazons. Their camouflage was all wrong unless you were deliberately trying to hide in this environment.The only people I knew who would do something like that without a plethora of modern weapons being evident; thus being the Seven Pillars; were the Ninja![in Japanese] "Hey there, are you looking for me?"[in Japanese] "Yes we are, Ishara-sama," a feminine voice answered. "Where is your companion? We are supposed to make a good faith effort to save them as well.""Wait... who hired you?""Well, it is supposed to be something of a secret so tell no one, but it was your brother," she replied in thickly accented English. With a few flashes of steel in the moonlight and I was a free Amazon once more."Were did the other two go?""Covering your tracks and laying out a few nuisance traps to confuse the two following you.""Your body feels... awfully familiar," I hazarded conversation of another sort."I am Miyako's older sister; and married. Happily so though I have been repeatedly reminded of your... horn-dog status. It is 'horn-dog' correct?""Yeah," I sighed. "That's me. Let's go find Felix before he gets hopelessly lost."By this time the other two had made it back to us, expertly covering my tracks; they were not leaving any; because, you know, they were ninjas. By the looks of things it must have seemed I flew away because I had simply vanished as well. I wish I could have hung around long enough to see the looks of consternation on the pursuing Amazons' faces, but I had real work to take care of."So basically, my Brother, the Great Khan, has hired three ninja to help me win," I whispered as we made our getaway into the moonlit darkness."Oh no," I could have sworn she smiled, "There are seven of us. We each have other tasks to perform, be it carry extra equipment, or scouting ahead to make sure we don't bump into any more of your girlfriends.""They are not my girlfriends... yet... maybe," I shrugged."Don't make me hit you," she whispered back. "I will hit you if you cheat too much on my little sister. She is so impressionable you know.""Oh... boy," I groaned. A protective older sister while I was on a time table. "Is all of your team female?" I asked instead."Yes. When dealing with our allies the Amazons it was considered the diplomatic thing to do. Now we most move like the autumn breeze over the grass, Ishara-sama.""Please, call me Cáel . What's your name?""Not something I can reveal while on a mission. My name in the team is 'First' as I am the team leader.""I could call you Hatsuyuki," I kept going. Hatsuyuki meant 'First Snow'. We were angling in a different direction suggesting to me we had come across Felix's path and were racing to catch him."I will help you out a bit," she chuckled ever so slightly. "Every woman on the team is a sister, or sister-in-law of Miyako, so we have all heard the tales of your exploits and been suitably warned by Grandmother to not fall for your... reindeer games.""Wow... cut off at the knees before even leaving the starting gate," I frowned."Please concentrate on the task at hand Ishara-sama," she whispered then, "Four more ahead of us. I swear they must have some sort of divine assistance as well.""Cheating bitches of all cheating bitches," I quietly cursed. Hatsuyuki put her hand over my mouth despite the low volume of my words.I risked a peek. It was fucking Elsa and Rachel and they were having a pow-wow with Tormé Maeve and Parul Nammu. By the rules of the Great Hunt, no Amazon could subdue, or otherwise hinder any other Amazon; as long as they didn't have a male. Then all bets were off. After a while the two teams flipped a coin and departed in different ways... which were eerily close to our actual track.The moment they were safely away, we took off once more at a steady jog. Mind you, I was in pretty damn good shape... and these little ninja babes were threatening to run me into the ground such was their stamina. The big thing was breath control. We had to be prepared to be utterly still at a moment's notice. Every Amazon around us was as hunter of some sort, be it of big game, or of humans.Even with their precautions we found ourselves being tracked by Daryna Šauška and Yatta Oxóssi within the hour. Exactly what they were tracking wasn't known to me and was a source of consternation to the Ninja. It was impossible to outrun horse-bound foes at our current pace and if we moved faster, the odds of our enchantment failing would drastically increase."Fuck!" I hissed."What?" Hatsuyuki made brief eye contact then scanned around for whatever threat I might have detected."They are tracking the magic of the enchantment," I enlightened her."Are you sure?""Alal; my Grandfather is," I held her eyes this time. "Honestly, I was going through the Rolodex of my mind when this thought occurred to me. I think it was a mystic rite the Egyptians invented millennia ago, but he knows it.""What is the counter?""I don't know," I sighed, "but I do know your movement is leaving a magical trail behind which glows like the failing light of a sunset to the searcher."Hatsuyuki whispered some arcane words which my ears failed to focus on while making several complicated hand gestures. She gave me one head nod then we took off, jogging in another direction though still angling to intercept Felix. I noticed the change immediately. Dry grass crackled beneath our feet and standing grass bent at our passage. I was the worst offender without a doubt.Later when we stopped for a break, 'Three' returned to tell us the followers had initially been confused by the loss of the spell energy betraying us, but then they dismounted and began tracking us on foot; slower yet still a persistent menace."New plan," I decided. "We set an ambush for them.""We can't do that, Cáel ," Hatsuyuki informed me. "We are forbidden to directly confront our foes."My mind barely hesitated in its skullduggery."But if I confront them, could you steal their horses?""Yes," she grinned once more, or so I thought. "Then set up a field of simple traps with a path I can maneuver through so I can lose them once I have their undivided attention. Can you do that?""Yes," and another smile."Let's get on it," I grinned back. I could tell she was warming up to me. After all, I wasn't pressuring her to save me, or violate her Contract. Instead I was thinking on my feet and utilizing what they were best at to avoid my enemies.[in Japanese] "Team, here is what we must do," Hatsuyuki gathered her girls together and laid out what they needed to accomplish.Twenty minutes later, the ambush was set and the two ladies walked right into it. Apparently the idea I would fight back so aggressively hadn't occurred to them. I smashed straight into Daryna first, knocking her down and running past her. Instinctively she jumped up, cursing me even as she gave chase. For an instance Yatta hesitated, considering mounting up and giving chase, or pursuing on foot. Rapidly riding a horse even in this partially moonlit night was risky so she decided to join Daryna on foot as I raced away. She did grab her lasso first though. Seeing as Daryna was following in my footsteps, it was Yatta who stumbled into the first series of traps, spraining her ankle in the process.Hearing that, I took a quick detour, allowing Daryna to catch up if she cut crossways in her pursuit. Predictably she did so and crashed into her own series of traps while I continued to beat feet out of there. As Daryna untangled herself from the 'spider web' trap; really just a tangle of silk strings; she heard the horses neigh and then take off. The ninja had exploded smoke bombs in the horses' faces to accomplish this feat.By the time Daryna stood up, I was long gone in the foot race. She carefully picked her way back to Yatta, helped her up and then worked her way back to find their saddles cut loose and packs set aside... and their horses long gone as well. From what 'Five' related to us later, Daryna elected to take after their lost steeds while Yatta treated her sore ankle. 'Five' didn't hang around to see how long it took Daryna to return with their mounts. The rest of us had successfully slipped away by that time.Reunited.By the time we had reunited with Felix he had already discovered our next Treasure Trove; more grain, a compass and a map of the whole region. Woot! We still only had one mount until an hour past sunrise when our two steeds came trotting into our brief camp. Now we had three horses. We elected to release Carla's mount to find its way back to her mistress... eventually, we hoped."Care to explain the entourage?" Felix joked."Somebody who is somebody loves me," I shrugged. "I can't tell you who though. I've been sworn to secrecy.""Damn... five female ninja. We have got to not waste this opportunity.""I am so onboard with that plan," I grinned, "but it going to be tough. Most of the only speak Japanese and they are all related to a girl I've already knocked up.""So they all know what a stud you are, Cáel ," Felix laughed. "Give it time and they'll be begging for it. I know the type. Fit, but silent with minimal social skills. They want to know all about how you seduced their sister, cousin, what have you.""God, I hope so," I groaned. "All this abstinence is driving me crazy.""Me too," he chuckled. "Me too."Oh, what we had planned was horribly irresponsible. We had the inaugural First Great Hunt to win for all Mankind after all. Still, it took only three elements to be effective; a stream, river, or lake of some kind to bathe in; to convince the ninja we had to take a bath to remove any scent the Amazons who captured us may have sprayed on us; and the ninjas' willingness to believe such an outlandish excuse to get naked. Once they saw us naked nature would take its course.Well, despite our awesome masculine arsenals... we got nowhere. The ninja babes didn't buy our excuses, blew away our pseudoscientific ramblings (pheromones don't work that way, they insisted) and seriously; we didn't really have the time. So while putting our shirts back on and then going for our boots, two more Amazons came our way. We barely had the warning time to seek cover when Elsa and Rachel came riding down the stream, looking each way for any signs of us.Thanks to our horses remaining perfectly still as well, they gradually moved past our hidey-holes and out of our view. The second the ninjas gave us the 'all clear' we hurriedly finished dressing then headed off in a different direction. The last two Amazons I wanted to confront were Elsa and Rachel. I liked Rachel too much and quite frankly was too afraid of Elsa.Once more we risked using some Ninja Magics to aid our passage through a light, early morning rain. This one put off a confusing area of tracks which were both difficult to follow; Amazons were no dummies; and included our chosen pathway to the next treasure trove. Shortly after an overcast noontime Sun, we hunkered down for a few hours and took a short nap.I would have liked to sleep longer, but according to the two ninja who had stood watch, the whole area appeared to be crawling with Amazons out and about, mounted and dismounted and following our misleading trails, but still being close enough around to make traveling above the canyons frankly impossible. Felix and I had a meeting of the minds with Hatsuyuki.Sending two Ninja off on our steeds wouldn't work because at least one group of the opposition had our binoculars and none of the Ninja could pass for us under such scrutiny. In fact, we couldn't come up with a single plan which guaranteed us a chance to move about unseen. So, we came up with a crazy plan instead. I would take off on Peppermint in an elliptical path meant to draw off as many Amazons as possible.It had to be me because a few of the Amazons might not pursue Felix if he tried the same stunt, focusing on capturing Ishara first... so Ishara had to be the one to play decoy. We shook hands, hugged then scouted around for the best opportunity for me to make a bolt for it... then off I went. What the Ninja planned to do wasn't revealed to us though I had a feeling they weren't enamored with my plan.Peppermint and I came out of the closest draw and set off with a meandering gate; we would need all the speed she could muster soon enough. Unthinkingly, I had also stumbled across an added bonus to my plan. Me and my dumb luck. See, all the Amazons anywhere close to me at the start had been pressing their mounts hard for a day and a half now plus hadn't spent any time last night sleeping whereas me and Peppermint were relatively well fed and watered as well as well rested.Still, my initial sense was that I was simply fucked. All across the plain, Amazons noted my presence within a minute and began moving to hem me in. I imagine once I was unmounted and bound, the grand melee to see who would claim me would begin. I counted twelve of the fine ladies and while none were directly ahead of the direction I was heading in, some were far too close for me to hold out much hope.I didn't give up though. I wasn't in me and apparently it wasn't in Peppermint either. She picked up the pace instinctively when I leaned forward and off we went. Incrementally, all thirteen steeds picked up their speeds. I wasn't going to make it... and then it got worse. Coming out of a draw to my front-right was none other than Ella Mielikki.See appeared as surprised to see me as I was to see her, but that didn't last. She whipped out her lasso and spurred her mount to go faster. She was going to cut me off. I had no out in any other direction. All I had was a plain full of grass and thunderclouds in the distance; just too far away to do me any good.'Remember who you were...' came unbidden to my mind.I leaned forward and began whispering in Peppermint's ear in a language I did not know... but three thousand years ago it had been the language of horse peoples like the Scythians who taught it to their noble young... and so had another people long forgotten by history... the Medians. The words spilled out of me until all that was left was the final benediction; words that would bind man and mount together.[Median] "For Aya," I whispered.Remember who you were; wasn't meant for me. It was for the hundreds of Median steeds my Grandfather had ridden into battle... with his comrades-in-arms for over a thousand years two thousand years ago.Ella was whirling the lasso over her head. We were so close I could read the prayer to Mielikki on her lips as she strove to close those last few hoof-falls. The lasso flew through the air...Peppermint took off in a burst of speed utterly unlooked for. Her ghostly white plume rose majestically over her head; Grandfather's symbol... and now mine. The thunder of a hundred such steeds filled my ears with their power as we pulled away from the falling lasso... now less than a foot... too short. She had missed us and with that throw, passed the last chance the Amazons had to catch me.Rachel would later tell me they were all completely aghast at the pace Peppermint set as we rode past Mielikki, easily outdistancing her thus everyone else. We had escaped them and they knew it. They didn't know how and the looks of utter disbelief the Amazons behind me exchanged left them no doubt I had led them a merry chase only to vanish in a whirlwind of dust as I raced all the way into the storm-burst. Gone, gone, gone.Rachel told me she had then turned to Elsa and laughed heartily."I should have given him my honor blade," she chuckled, "because unlike the rest of you, I knew better.""But, what did he do?" Elsa had asked, truly curious and a bit frustrated."Just being Cáel ," Rachel had shaken her head as she replied. "Just being Cáel ."[Sunday]It was a thick, pounding rain as promised. No one could ride in this. Visibility was down to a few yards and the ground had turned into a morass. Only the greyness of the clouds betrayed the coming of day to us while our final treasure trove; a compass, map and coordinates for the rescue; pointed us in the proper direction... us and thirty Amazons.In our favor, the Ninja threw up a marching cordon around us so we didn't walk into any ambushes, and any Amazons not already at least even with us in the distance separating us from our evacuation point had a chance of catching us. Again, no Amazon worthy of their name would ride in weather like this and in a foot race, we men actually finally had the advantage.I wish I knew who was closest so I could plan accordingly. In strictly hand to hand combat, Felix and I had the advantage on over half those we were confronting. While most excelled at being hunters, beating up their prey with hands and knives wasn't normally their second best feature. No, they were fine combatants, just not in Felix's, or my, league.But then there were the Amazons like Tormé Maeve and Elsa Zorja who could kick our asses without a doubt, and planning how to fight them required a completely different game plan."What's on your mind?" Felix leaned in and shouted into my ear."This ain't over. Not only do we have to reach the evacuation site within a twenty minute window, we have to hope a half-dozen Amazons aren't waiting there for us."Felix nodded."Who is going to be the worst team?""Elsa and Rachel. I'm not sure I can beat Rachel and I'm damn sure I can't beat Elsa," I answered."Leave Elsa to me then. While I've never fought her before, she's also never fought me," he reasoned. "My best bet is an all-out offense; holding nothing back and hope I can outmuscle her before she pulls some surprise on me.""That's about right," it was my turn to nod.One of the Ninja came running back to us."There are two Amazons ahead of us going in the same direction. What do you want to do?"I looked to Felix who cracked his knuckles. He was right too. We didn't have enough time left to race around them; not in this mud; so jumping them and putting them down was our best bet.Bleeding.Our fists were bleeding, I had a knife wound on my left thigh, and Felix's nose was most likely broken, but we had put down two pairs of Amazons in the closing hour of the Great Hunt... and we were still free. We had even recorded the coordinates of where we left the four bound Amazons because leaving them all tied up in these conditions didn't seem fair.So far we had put down Niranjana Ereshkigal and Anna Cybele whose strategy was to figure out where the evacuation point was and then set up an ambush close by, and our old buddies, Tormé Maeve and Parul Nammu, who had been racing up to the evacuation point after some piece of divine intervention. They stumbled into us as we were binding up the first two.Thanks to the Ninja we had a moment's warning before they jogged right into us. It was on! Felix immediately challenged Tormé while I circled Parul, each seeking an advantage. Unfortunately, Tormé began cleaning Felix's clock so spun around and we switched partners."I wanted it to be me and you," she snarled."I was hoping to miss you entirely," I replied. She laughed and closed... and then slipped in the mud and slid right into my knee strike. Before she could clean the cobwebs from her head, I had landed three solid fist strikes to her jaw, rendering her incapable of immediate resistance; one tough chick! I quick glance back to Felix showed me he had Parul well in hand, so I quickly bound Tormé up and took her honor blade so she wouldn't be cutting herself free too soon.After we had Parul secured, Felix slapped me on the back and laughed."You bastard, I saw that," he chuckled. "She slipped.""I'll take it," I was unapologetic. Explaining to Felix how she was Katrina's #1 assassin would take too long. I'd leave it to Katrina to warn him how dangerous dating her would be.And then we heard the helicopter... and looked at our watches. It Was 11:48! We raced up the last bit of the slope to see the helicopter finish its descent. We'd made it... and then we saw Elsa and Rachel climbing up the slope beside us, disguised as we were by the downpour."Cáel !" Elsa screamed out my name. Rachel simply charged Felix wordlessly.I drew Tormé's honor blade and faced Elsa down. "Do you honestly think you can defeat me?" Elsa laughed. "Because Cáel , you cannot. You are already beaten, bruised and bleeding. Surrender and I promise to be gentle.""On any other day, I would agree with you, but this is not like any other day," I held my captured small knife out in a fighting stance."Today... today I have my Grandfather's knowledge and my Father's boundless spirit, Elsa. Today; you cannot defeat me. Come at me and find out, if you must." My stance flowed into an alien design... which came from a time when knives were the only close combat weapon anyone was lucky enough to have. My knife raised up over my head yet still pointing at my opponent while my empty left hand pointed at my foe.Then it occurred to me... if I could withstand the pain, I could grab her blade and hold it in place while I slashed down with my own ceremonial weapon. I could regenerate the damage; that was my edge and this was a fighting stance my Grandfather had perfected with that knowledge when all blades were either sharp stones, or smelted copper.I could see Elsa studying me rapid-quick before she made her lunge. It was so On! The first series of slashing strikes saw me barely missing having my hand cut open. I wasn't so lucky my second time around. Elsa sliced my ring finger to the bone."Damnit, Cáel !" Elsa snapped. "If you are going to fight me, at least use the training Pamela gave you. I have no idea what this crazy stance is supposed to show, but I think it is nothing more than your made-up style again. This time I am going to really hurt you if you don't surrender... Right Now!"Yeah, Elsa was upset she had to actually hurt me. I sensed that in her. Still, the pain quickly receded and I continued to stalk her... silently and with great determination on my face. No response was necessary and I was sure my quietude was unsettling her even more. On the next exchange Elsa moved so fast I couldn't track her blade. Still, I moved my empty palm across to stop her most likely angle of attack.I was wrong. By shifting my entire body to stop her slash, I put myself in the wrong positon; closing the distance between us and intercepting her surprise backslash with my left side at the kidney level. Ouch! Motherfucker! I grunted but used my positioning disadvantage as an advantage. As Elsa's hand recoiled from the dire wound she had given me, I reached out with my left hand and grabbed her wrist.My right hand came down attempting to slash her wrist in this exchange. She caught my right wrist in her left hand. Our bodies collided then my forward momentum slammed into her form and we both fell over. She rolled so we ended up crashing down on our sides, but I refused to release my hold while driving my blade ever downward.I didn't have much advantage over Elsa, but I was superior in upper body strength. It was my old buddy except coming out in my favor today. Slowly my blade inched toward its target."How... can... you... still... be... fighting?" Elsa ground out between her teeth."I am Ishara," was my reply. "The power of the goddess runs through me," I added a lie meant to confuse and dishearten her.She tried to break away by rolling around. I wouldn't let her. I tangled my legs up with hers until we were one conjoined mess. Then she surprised me with a head-butt right as the option was just occurring to me. She smashed my nose. There was blood everywhere, but I wouldn't relent on my hold. Instead, I followed up her head-butt with one of my own.Elsa caught mine with the hardest part of her forehead instead. Our skulls collided. I refused to feel the pain so while she was still reeling from that contact I smashed forward once again; this time impacting her temple and really shocking her. I had to have seemed like a monster to Elsa by this point in our bout; I could feel no pain and no infirmary would hold me back.Lacking every other point of leverage, she went for the 'Tried and True'; her knee impacted my precious gonads and for just that instance, my hold on her weakened. She broke free then rolled away."Stay down," she almost screamed at me. I didn't, instead rising up and resuming my archaic stance once more."This is going to hurt you a whole lot more than me," she promised next. Just then we both heard a titanic scream to my left. By the sound of the grunt which followed, I realized Felix had connected with one of his powerful kicks to Rachel's ribs. I used the positional advantage to charge. We collided once more, each one's opposite hand clamping down on the other's knife hand.While standing, we pushed each other back and forth, attempting kicks and foot stomps all the while my knife approached Elsa's collarbone. We were both too on guard for head-butts to pull one off this grapple, but I didn't need it... because we were in fact, grappling and I had a whole martial art devoted to grappling; Brazilian Jujutsu!I dropped Tormé's honor blade and flipped us around so I landed on top of her. Her blade drew a bloody line along my hip, but not enough damage to cause me any consternation. I could see it in her eyes, the moment we landed in the mud. She realized her mistake by allowing me too close, but the last time she had let that happened she had succeeded in stabbing me in the kidney, so she was taken off-guard for just that instance."Yeah," I chortled, "Just recalling my Brazilian Jujutsu aren't ya?""I can beat it," she ground out."You and an MMA Army," I growled back. She was in danger of having me roll her over... then it would be light's out!Right then Rachel and Felix came crashing down on the two of us, breaking my concentration and my hold. The four of us rolled up and separated once more.Rachel moved to Elsa's side while Felix helped me stand."We are running out of time," Felix informed me. We were. That appeared to be Rachel and Elsa's strategy all along. Keep us occupied for the remaining... eighteen minutes... damn was I out of breath and hurting."Switch," Felix tapped me on the forearm. "I got this."He didn't and he knew he didn't. For some god damn unknown reason, Felix was doing a selfless act for the first time in his life and I couldn't comprehend why."She'll destroy you," I pointed out."You're bleeding; badly," he stated, "and failing fast.""Listen to your friend," Rachel interjected herself into the conversation. Worse, she stepped aside and clearly indicated she would let me pass."Rachel!" Elsa snapped."He's earned it. For the past eighty-four days and then some, Cáel has earned; our respect," Rachel reminded us."Okay," I acknowledged the act of kindness. I moved behind Felix so he could screen me from Elsa... then shoved him as hard as I could across the muddy surface toward freedom. The look he sent back my way was priceless. Reluctantly, he looked back once then jogged to the helicopter and the rewards he deserved for surviving against so many for so long; just like me, but without the Goddesses and my troop of ruthless Amazon allies..."Two on one," I joked."No. I've surrendered my trophy," Rachel smile to me was emotionally crushing."Fine," Elsa nodded then, "Let's continue." This time I didn't have a knife.When we collided this time, she didn't hesitate to stab me in the left pectoral; above the heart, but not by much. I failed to catch her wrist and realized I was all out of game. My regeneration couldn't tackle both bleeding wounds and I was beginning to feel woozy.Elsa fell back."Surrender, Cáel ," her own voice had softened."Never surrender," I laughed back then I began to sway.This time as Elsa closed, she went for the grapple as well. I countered as best I could, but my reflexes were slowing down too. I wasn't going to make it then something tackled us both, slamming Elsa into my chest, stunning her."Felix... you came back," I groggily mumbled as Felix hammered Elsa hard, twice in the temple."You would come back for me. I see that now," he confessed. He half pulled, half-dragged me to our waiting chariot. The clock was a 'ticking."Rachel," I looked over to the other combatant. She hadn't started advancing on us like she should have."Go," she waved us away. "Today... today you have won your freedoms. Now go."What honors Rachel had passed over for whatever reasons were unknown to me. I was terrified she had done it out of love for me. Terrified because I felt so unworthy of such devotion and affection.Yet, Felix and I had made it and as the helicopter took off, I could sense the tension leave my body. My wounds were indeed healing and my blood supply, so witlessly spent was returning to me. Felix leaned into me as the nice Epona medic aboard our ride began to administer her traumatic injury training. I winced because it felt appropriate, not because I was allowed to feel any of the passing pain."You are a Runner now," I looked over to Felix. "Welcome aboard.""Sure thing, Ishara.""Ha," I chuckled. "Call me Cáel . You have earned that right.""I imagine there is something to that," he nodded. "Tell me what it is when you get the chance.""I will," I promised. "That and a few thousand other critically important things none one else will bother to teach you. As the saying goes, 'you've earned it'."Thus Ends The First Great HuntNow onto the final chapter of the First Part of Cáel 's journey.By FinalStand for Literotica.

A független kutatók Magyar Péterék előnyét mérik, a szakma kormánypárti része élesen bírálja őket ezért. Magyarék azonban hiába vezetnek egyelőre: a választásokig még szűk tíz hónap hátra van. Hann Endrét Kacskovics Mihály Béla kérdezte. Az adásban említett közvéleménykutatás eredményeit itt tudod megnézni: ⁦https://hvg.hu/360/20250703_median-felmeres-se-jobb-se-baloldali-magyarok-centristak-tobbsegben-tisza-dk⁩ ⁦https://hvg.hu/360/20250626_Median-politikusok-alkalmassaga-Orban-Viktor-Magyar-Peter-Dobrev-Klara⁩ ⁦https://hvg.hu/360/20250625_Median-Tisza-Part-ellenzeki-partok-kozvelemeny-kutatas⁩ ⁦https://hvg.hu/360/20250619_median-felmeres-tisza-fidesz-part-preferencia-nagyvarosok-falvak⁩ ⁦https://hvg.hu/360/20250618_A-Tisza-annyival-vezet-a-Fidesz-elott-amennyivel-Orbanek-vertek-2022-ben-Marki-Zay-hatos-fogatat⁩ Olvass még több prémium tartalmat a hvg360-on! Próbáld ki a hvg360-at most féláron

In this JCO Article Insights episode, host Peter Li summarizes "Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST" by Pérol et al, published April 03, 2025, followed by an interview with first author, Dr Maurice Pérol. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's editorial fellow, and today I am joined by Dr. Maurice Pérol on “Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST,” by Pérol et al. At the time of this recording, our guest has disclosures that will be linked in the transcript. Before we start our interview, I want to give our listeners a quick summary of the TRUST study. For those tuning in, the TRUST study is a phase II, single-arm, open-label, nonrandomized, multicenter trial looking at the efficacy and safety of a novel, next-generation ROS1 TKI, taletrectinib, in advanced ROS1-mutated non–small cell lung cancer. While a relatively rare mutation, the prevalence of ROS1 mutations ranges from 0.9% to 2.6% of patients, with a third of patients presenting with brain mets at diagnosis.Current FDA-approved therapies include crizotinib, entrectinib, and repotrectinib, which have varying degrees of efficacy, in-coming with trade-offs in CNS penetrance and safety with newer generations, particularly in the realm of neurological side effects, highlighting an unmet need in this arena. A total of 273 patients with advanced non–small cell lung cancer with confirmed ROS1 mutation were recruited for this study. 160 patients were TKI-naive, while 113 were TKI-experienced with either crizotinib or entrectinib. Patients with asymptomatic brain mets were also allowed to enroll. In the TKI-naive arm, the median age was 57, with 91% of patients having stage IV disease, 20% having no more than one cycle of chemo, and 23% having brain mets at baseline. In the TKI-experienced arm, the median age was 53, with 97% having stage IV disease, 37% having received prior chemo, and about 50% having brain mets. Furthermore, about 10% of the study population had received entrectinib, while more than 90% had received crizotinib. About 10% had a known G2032R acquired resistance mutation. Taletrectinib was dosed at 600 mg daily until disease progression or unacceptable toxicities. The primary endpoint was overall response rate, with secondary endpoints being disease control rate, duration of response, time to response, and progression-free survival. For those with brain mets, intracranial overall response rate and disease control rate were also assessed. Median follow-up time was about 21 months in both cohorts. In the TKI-naive cohort, the overall response rate was 89%, with 8 patients achieving a complete response. Disease control rate was 95%, with a median duration of response of 44.2 months. Time to treatment response was about 1.5 months. Median progression-free survival was 45.6 months, with 52.6% not having progressed at 3 years. While overall survival data were immature, 66% of patients were still alive at 3 years. In the pretreated cohort, overall response rate was 56%, with 5 patients achieving a complete response. Overall response rate was 53% for those who were crizotinib-pretreated and 80% for the entrectinib-pretreated patients. Disease control rate was 88%, and median duration of response was about 16.5 months. Time to treatment response was also 1.5 months, and median progression-free survival was 9.7 months. Median overall survival was not reached, but 77.5% of patients were still alive at 1 year. Responses were consistently seen across subgroup analyses. 17 TKI-naive and 32 TKI-pretreated patients had measurable brain mets. In the TKI-naive arm, intracranial overall response rate was 77%. Disease control rate was 88%, and duration of response was 15 months. In the TKI-pretreated arm, intracranial overall response was 66%, with one patient achieving complete response. The disease control rate was 94%, and duration of response was about a year. For the 13 patients who had a known G2032R mutation, a 62% response rate was noted. Most common treatment-related side effects were AST/ALT elevation, nausea, and vomiting, with most being grade 1 or 2. Most common neurological side effects were dizziness, dysgeusia, and headache. Again, most were grade 1. QTc prolongation is another important adverse event to note, occurring in about 18% of all patients. Discontinuation rate from treatment was only 7%. There were three treatment-related deaths in this study: one from hepatic failure, one from pneumonia in the naive arm, and one from liver dysfunction in the pretreated arm. Dr. Peter Li: Maurice, thank you so much for joining us today to talk about your paper. Would you mind just giving yourself a brief introduction to the listeners out there of who you are? Dr. Maurice Pérol: So, my name is Maurice Perol. I'm a thoracic oncologist working in the Cancer Center of Lyon in France. And I'm involved in clinical research in thoracic oncology. I've been involved for many years now. Dr. Peter Li: Okay. And for listeners out there, don't forget, he's also the primary author of the paper that we just talked about. So, Maurice, let's begin. Can you tell our listeners what is the significance of your study? Dr. Maurice Pérol: Well, the results of these two large phase II studies - TRUST-I, which has been conducted in China, and TRUST-II, which was a global, worldwide phase II study - so, the results place taletrectinib as the TKI with the most favorable efficacy-tolerability ratio of the available ROS1-targeting TKIs, especially in frontline therapy. And this is based on the response rate, which was very impressive, the CNS penetration with a great CNS activity, the duration of response with a compelling 45 months median PFS in frontline setting. The level of activity in pretreated patients after crizotinib or entrectinib was also impressive and similar to that of repotrectinib, for example, but with a more favorable neurological tolerance profile. The toxicity is mainly represented with grade 1 or 2 transaminase elevation, but without clinical symptoms, and GI toxicity, but mainly grade 1 and 2. The neurological toxicity is low, especially for dizziness, showing that taletrectinib spares TrKB in a large part. And finally, there is also a decrease in toxicity over time, especially for GI toxicity and liver toxicities, which allows a very long and a prolonged administration, which is very important in this setting. Dr. Peter Li: These are all excellent points. Can you tell the listeners if there are any limitations that we should be concerned about, about this study? Dr. Maurice Pérol: Sure. This data comes from single-arm phase II studies. So, this is not comparative data. And a phase III trial, which compares taletrectinib to crizotinib, is ongoing to evaluate the superiority of taletrectinib over the standard of care. Another limitation comes from the lack of systematic brain imaging at each tumor evaluation in patients without brain metastases at baseline, not allowing to assess the intracranial PFS in all patients, and which did not allow us to assess the CNS protective issue from taletrectinib, especially in patients without brain metastases at baseline. Dr. Peter Li: Another question that I have is, with this novel TKI now available, how would you recommend the sequencing of these drugs? Would you start with someone on an alternate TKI and then reserve taletrectinib second line or later? Or would you use it upfront? Or does it depend? Dr. Maurice Pérol: Well, it is a very important question, as we have now different available TKIs. Looking at the efficacy-toxicity balance, I would strongly favor the use of taletrectinib in frontline setting, in first line. The response rate, the CNS activity, the duration of response with a very compelling 45 months median PFS, and moreover, the good tolerance profile over time are strong arguments in favor of giving taletrectinib in frontline. Generally speaking, the use of the most active agent as frontline treatment in lung cancer depending on an oncogenic addiction is probably the best way to improve the patient's outcome. This is true for patients with EGFR mutation, for patients with ALK fusions, and this is probably also true for patients with ROS1 fusion. So, I would probably argue in favor of a frontline use of taletrectinib. Dr. Peter Li: Listeners are going to ask, well, if you use taletrectinib upfront, then what are you going to use second line once they progress? Dr. Maurice Pérol: Well, we have some new compounds which are under development today. For example, the NVL-520, which is a very interesting compound, which seems also to be active in case of resistance mutation. But I do think that we have to use the best-in-class TKI in frontline because, you know, the extension of PFS after acquired resistance you can obtain with a second-line TKI is always shorter than the benefit you can obtain by using the most active agent in frontline. And this is true for the majority of oncogenic addiction in lung cancer. Dr. Peter Li: That makes sense. I also noticed that cognitive impairment wasn't listed in the safety table. Is that not an issue that you've observed at all with taletrectinib, or is it still an issue but less so because, like you mentioned earlier, because of its higher selectivity? Dr. Maurice Pérol: Well, this is a good question because we have some ROS1-targeting TKIs like repotrectinib, entrectinib, and even lorlatinib, with some neurological adverse events and some cognitive issues. Taletrectinib is a very selective ROS1-targeting TKI, and it spares very well the TrKB, for example, explaining that we did not observe any cognitive impairment with taletrectinib in the TRUST study, showing also with the low level of other neurological adverse events, dizziness, dysgeusia, for example, the high selectivity of the compound and the preservation of TrKB. So, this is very important when you consider the long duration of treatment in those patients with ROS1 fusion. If you have to take a drug for more than 2, 3, or 4 years, of course, the neurological adverse events are very important, and they can clearly impair the quality of life. So, this is a very important point, the very low level of neurological toxicity of taletrectinib. Dr. Peter Li: And I think that goes to say why you would favor using it frontline as well compared to entrectinib or repotrectinib. Last question that we have for you is: well, what's next? You mentioned there's a phase III trial comparing it to crizotinib. I think one of the questions that a lot of us would have is: why not compare it to one of the newer agents as a comparator arm? Dr. Maurice Pérol: Well, this is a good question. Crizotinib remains the standard of care in many countries for ROS1-positive advanced non–small cell lung cancer outside of the US, especially in Europe, and in particular in patients who do not have brain metastases at diagnosis. Entrectinib has a better CNS penetration, but it did not achieve a better PFS than crizotinib in phase I/II trials, and clearly, it has a less favorable tolerance profile with weight gain, edema, and neurological adverse events. Repotrectinib has overall a level of activity which seems close to that of taletrectinib. So, it makes it difficult to consider a comparative trial that would, for example, test taletrectinib in comparison with repotrectinib because this kind of study would need a very large number of patients and a very late readout. Considering if you have a median PFS of more than 3 or 4 years, it would be very difficult to have results in before 4-5 years. So, from a pragmatic point of view, the comparison of taletrectinib to crizotinib is probably the best way to evaluate in a phase III setting the level of activity of taletrectinib, especially in the CNS, because this study will probably allow us to assess the CNS protective effect of the compound for patients without brain metastates at baseline. So, I think probably it's a pragmatic study that will allow us to confirm the high level of activity and the good tolerance profile of taletrectinib. Dr. Peter Li: Well, thank you, Maurice, so much for speaking about the JCO article, “Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST,” and for all your valuable input today. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Big O talks Crypto 062725

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss important advances in the treatment of prostate, bladder, and kidney cancers that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News.  I am delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of the GU Center at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that were presented at the 2025 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode.  Jeanny, it is great to have you on the podcast. Dr. Jeanny Aragon-Ching: Oh, thank you so much, Neeraj. Dr. Neeraj Agarwal: Jeanny, let's begin with some prostate cancer abstracts. Let's begin with Abstract 5017 titled, “Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer.” Can you walk us through the design and the key findings of this first-in-human trial? Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this study, presented by Dr. Capucine Baldini, introduces pasritamig, a first-in-class T-cell redirecting bispecific antibody that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. KLK2 is also known as human kallikrein 2, which is selectively expressed in prostate tissue. And for reference, KLK3 is what we now know as the PSA, prostate-specific antigen, therefore making it an attractive and specific target for therapeutic engagement. Now, while this was an early, first-in-human, phase 1 study, it enrolled 174 heavily pretreated metastatic CRPC patients. So many were previously treated with ARPIs, taxanes, and radioligand therapy. So given the phase 1 nature of this study, the primary objective was to determine the safety and the RP2D, which is the recommended phase 2 dose. Secondary objectives included preliminary assessment of antitumor activity. So, pasritamig was generally well tolerated. There were no treatment-related deaths. Serious adverse events were rare. And in the RP2D safety cohort, where patients received the step-up dosing up to 300 mg of IV every 6 weeks, the most common treatment-related adverse events were low-grade infusion reactions. There was fatigue and grade 1 cytokine release syndrome, what we call CRS. And no cases of neurotoxicity, or what we call ICANS, the immune effector cell-associated neurotoxicity syndrome, reported. Importantly, the CRS occurred in just about 8.9% of patients. All were grade 1. No patients required tocilizumab or discontinued treatment due to adverse events. So, this suggests a favorable safety profile, allowing hopefully for outpatient administration without hospitalization, which will be very important when we're thinking about bispecifics moving forward. In terms of efficacy, pasritamig showed promising activity. About 42.4% of evaluable patients achieved a PSA50 response. Radiographic PFS was about 6.8 months. And among patients with measurable disease, the objective response rate was about 16.1% in those with lymph node or bone metastases, and about 3.7% in those with visceral disease, with a median duration of response of about 11.3 months. So, altogether, this data suggests that pasritamig may offer a well-tolerated and active new potential option for patients with metastatic CRPC.   Again, as a reminder, with the caveat that this is still an early phase 1 study. Dr. Neeraj Agarwal: Thank you, Jeanny. These are promising results for a bispecific T-cell engager, pasritamig, in prostate cancer. I agree, the safety and durability observed here stand out, and this opens the door for further development, possibly even in earlier disease settings.  So, shifting now from immunotherapy to the evolving role of genomics in prostate cancer. So let's discuss Abstract 5094, a real-world, retrospective analysis exploring the prognostic impact of homologous recombination repair gene mutations, especially BRCA1 and BRCA2 mutations, in metastatic hormone-sensitive prostate cancer. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So this study was presented by Dr. David Olmos, represents one of the largest real-world analyses we have evaluating the impact of homologous recombination repair, or what we would call HRR, alterations in metastatic hormone-sensitive prostate cancer. So, this cohort included 556 men who underwent paired germline and somatic testing. Now, about 30% of patients had HRR alterations, with about 12% harboring BRCA1 or BRCA2 mutations and 16% having alterations in other HRR genes. Importantly, patients were stratified via CHAARTED disease volume, and outcomes were examined across treatment approaches, including ADT alone, doublet therapy, and triplet therapy. The prevalence of BRCA and HRR alterations were about similar between the metastatic hormone-sensitive prostate cancer and the metastatic castrate-resistant prostate cancer, with no differences observed, actually, between the patients with high volume versus low volume disease.  So, the key finding was that BRCA and HRR alterations were associated with poor clinical outcomes in metastatic hormone-sensitive prostate cancer. And notably, the impact of these alterations may actually be even greater in metastatic hormone-sensitive prostate cancer than previously reported in metastatic CRPC. So, the data showed that when BRCA mutations are present, the impact of the volume of disease is actually limited. So, poor outcomes were observed across the board for both high-volume and low-volume groups. So, the analysis showed that patients with HRR alterations had significantly worse outcomes compared to patients without HRR alterations. Median radiographic progression-free survival was about 20.5 months for the HRR-altered patients versus 30.6 months for the non-HRR patients, with a hazard ratio of 1.6. Median overall survival was 39 months for HRR-altered patients compared to 55.7 months for the non-HRR patients, with a hazard ratio of 1.5. Similar significant differences were observed when BRCA-mutant patients were compared with patients harboring non-BRCA HRR mutations. Overall, poor outcomes were independent of treatment of ARPI or taxanes. Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data reinforce homologous recombination repair mutations as both a predictive and prognostic biomarker, not only in the mCRPC, but also in the metastatic hormone-sensitive setting as well. It also makes a strong case for incorporating genomic testing early in the disease course and not waiting until our patients have castration-resistant disease. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. And I think this really brings home the point and the lead up to the AMPLITUDE trial, which is LBA5006, a phase 3 trial that builds on this very concept of testing with a PARP inhibitor, niraparib, in the hormone-sensitive space. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the AMPLITUDE trial, a phase 3 trial presented by Dr. Gerhardt Attard, enrolled 696 patients with metastatic hormone-sensitive prostate cancer and HRR gene alterations. 56% of these patients had BRCA1 and BRCA2 mutations. Patients were randomized to receive abiraterone with or without niraparib, a PARP inhibitor. The majority of patients, 78% of these patients, had high-volume metastatic hormone-sensitive prostate cancer, and 87% of these patients had de novo metastatic HSPC. And 16% of these patients received prior docetaxel, which was allowed in the clinical trial. So, with a median follow-up of nearly 31 months, radiographic progression-free survival was significantly prolonged with the niraparib plus abiraterone combination, and median was not reached in this arm, compared to abiraterone alone, which was 29.5 months, with a hazard ratio of 0.63, translating to a 37% reduction in risk of progression or death. This benefit was even more pronounced in the BRCA1 and BRCA2 subgroup, with a 48% reduction in risk of progression, with a hazard ratio of 0.52. Time to symptomatic progression also improved significantly across all patients, including patients with BRCA1, BRCA2, and HRR mutations. Although overall survival data remain immature, early trends favored the niraparib plus abiraterone combination. The safety profile was consistent with prior PARP inhibitor studies, with grade 3 or higher anemia and hypertension were more common but manageable. Treatment discontinuation due to adverse events remained low at 11%, suggesting that timely dose modifications when our patients experience grade 3 side effects may allow our patients to continue treatment without discontinuation. These findings support niraparib plus abiraterone as a potential new standard of care in our patients with metastatic hormone-sensitive prostate cancer with HRR alterations, and especially in those who had BRCA1 and BRCA2 mutations. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. This trial is especially exciting because it brings PARP inhibitors earlier into the treatment paradigm. Dr. Neeraj Agarwal: Exactly. And it is exciting to see the effect of PARP inhibitors in the earlier setting.  So Jeanny, now let's switch gears a bit to bladder cancer, which also saw several impactful studies. Could you tell us about Abstract 4502, an exploratory analysis from the EV-302 trial, which led to approval of enfortumab vedotin plus pembrolizumab for our patients with newly diagnosed metastatic bladder cancer? So here, the authors looked at the outcomes in patients who achieved a confirmed complete response with EV plus pembrolizumab. Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, EV-302 demonstrated significant improvements in progression-free and overall survival for patients previously treated locally advanced or metastatic urothelial cancer, I'll just call it metastatic UC, as a frontline strategy, establishing EV, which is enfortumab vedotin, plus pembro, with pembrolizumab as standard of care in this setting.  So, this year at ASCO, Dr Shilpa Gupta presented this exploratory responder analysis from the phase 3 EV-302 trial. Among 886 randomized patients, about 30.4% of patients, this is about 133, in the EV+P arm, and 14.5% of the patients in the chemotherapy arm, achieved a confirmed complete response. They call it the CCR rates. So for patients who achieved this, median PFS was not reached with EV+P compared to 26.9 months with chemotherapy, with a hazard ratio of 0.36, translating to a 64% reduction in the risk of progression. Overall survival was also improved. So the median OS was not reached in either arm, but the hazard ratio favored the EV+P at 0.37, translating to a 63% reduction in the risk of death. The median duration of complete response was not reached with EV+P compared to 15.2 months with chemotherapy. And among those patients who had confirmed CRs at 24 months, 78% of patients with the EV+P arm remained progression-free, and around 95% of the patients were alive, compared to 54% of patients who were progression-free and 86% alive of the patients in the chemotherapy arm. Safety among responders were also consistent with prior reports. Grade 3 or higher treatment-related adverse events occurred in 62% of EV+P responders and 72% of chemotherapy responders. Most adverse events were managed with dose modifications, and importantly, no treatment-related deaths were reported among those who were able to achieve complete response.  So these findings further reinforce EV and pembro as the preferred first-line therapy for metastatic urothelial carcinoma, offering a higher likelihood of deep, durable responses with a fairly manageable safety profile. Dr. Neeraj Agarwal: Thank you for the great summary, Jeanny. These findings underscore the depth and durability of responses achievable with this combination and also suggest that achieving a response may be a surrogate for long-term benefit in patients with metastatic urothelial carcinoma.  So now, let's move to Abstract 4503, an exploratory ctDNA analysis from the NIAGARA trial, which evaluated perioperative durvalumab, an immune checkpoint inhibitor, in muscle-invasive bladder cancer. So what can you tell us about this abstract? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in NIAGARA, presented by Dr. Tom Powles, the addition of perioperative durvalumab to neoadjuvant chemotherapy, gem/cis, significantly improved event-free survival, overall survival, and pathologic complete response in patients with cisplatin-eligible muscle-invasive bladder cancer. Recall that this led to the U.S. FDA approval of this treatment regimen on March 28, 2025.  So, a planned exploratory analysis evaluated the ctDNA dynamics and their association with clinical outcomes, which was the one presented recently at ASCO. So, the study found that the incidence of finding ctDNA positivity in these patients was about 57%. Following neoadjuvant treatment, this dropped to about 22%, with ctDNA clearance being more common in the durvalumab arm, about 41%, compared to the chemotherapy control arm of 31%. Notably, 97% of patients who remained ctDNA positive prior to surgery failed to achieve a pathologic CR. So, this indicates a strong association between ctDNA persistence and lack of tumor eradication. So, postoperatively, only about 9% of patients were ctDNA positive. So, importantly, durvalumab conferred an event-free survival benefit regardless of ctDNA status at both baseline and post-surgery. Among patients who were ctDNA positive at baseline, durvalumab led to a hazard ratio of 0.73 for EFS. So, this translates to a 27% reduction in the risk of disease recurrence, progression, or death compared to the control arm. In the post-surgical ctDNA-positive group, the disease-free survival was also improved with a hazard ratio of 0.49, translating to a 51% reduction in the risk of recurrence.  So, these findings underscore the prognostic value of ctDNA and suggest that durvalumab provides clinical benefit irrespective of molecular residual disease status. So, the data also supports that ctDNA is a promising biomarker for future personalized strategies in the perioperative treatment of muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Jeanny. It is great to see that durvalumab is improving outcomes in these patients regardless of ctDNA status. However, based on these data, presence of ctDNA in our patients warrants a closer follow-up with imaging studies, because these patients with positive ctDNA seem to have a higher risk of recurrence. Dr. Jeanny Aragon-Ching: I agree, Neeraj.  Let's round out the bladder cancer discussion with Abstract 4518, which reported the interim results of SURE-02, which is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure, Jeanny. So, Dr Andrea Necchi presented interim results from the SURE-02 trial. This is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by a response-adapted bladder-sparing treatment and adjuvant pembrolizumab in patients with muscle-invasive bladder cancer.  So, in this interim analysis, 40 patients were treated and 31 patients were evaluable for efficacy. So, the clinical complete response rate was 38.7%. All patients achieving clinical complete response underwent bladder-sparing approach with a repeat TURBT instead of radical cystectomy. Additionally, 51.6% of patients achieved excellent pathologic response with a T stage of 1 or less after neoadjuvant therapy. The treatment was well tolerated, with only 12.9% of patients experiencing grade 3 or higher adverse events without needing dose reduction of sacituzumab. Molecular profiling, interestingly, showed that clinical complete response correlated with luminal and genomically unstable subtypes, while high stromal gene expression was associated with lack of response.  These results suggest that sacituzumab plus pembrolizumab combination has promising activity in this setting, and tolerability, and along with other factors may potentially allow a bladder preservation approach in a substantial number of patients down the line. Dr. Jeanny Aragon-Ching: Yeah, agree with you, Neeraj. And the findings are very provocative and support completing the full trial enrollment and further exploration of this strategy in muscle-invasive bladder cancer in order to improve and provide further bladder-sparing strategies. Dr. Neeraj Agarwal: Agree. So, let's now turn to the kidney cancer, starting with Abstract 4505, the final overall analysis from CheckMate-214 trial, which evaluated nivolumab plus ipilimumab, so dual checkpoint inhibition strategy, versus sunitinib in our patients with metastatic clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So, the final 9-year analysis of the phase 3 CheckMate-214 trial confirms the long-term superiority of nivolumab and ipilimumab over sunitinib for first-line treatment of advanced metastatic renal cell carcinoma. So, this has a median follow-up of 9 years. Overall survival remains significantly improved with the combination. So, in the ITT patient population, the intention-to-treat, the hazard ratio for overall survival was 0.71. So, this translates to a 29% reduction in the risk of death. 31% of patients were alive at this 108-month follow-up compared to 20% only in those who got sunitinib. So, similar benefits were observed in the intermediate- and poor-risk groups with a hazard ratio of 0.69, and 30% versus 19% survival at 108 months.  Importantly, a delayed benefit was also seen in those favorable-risk patients. So, the hazard ratio for overall survival improved from 1.45 in the initial report and now at 0.8 at 9 years follow-up, with 35% of patients alive at 108 months compared to 22% in those who got sunitinib. Progression-free survival also favored the nivo-ipi arm across all risk groups. At 96 months, the probability of remaining progression-free was about 23% compared to 9% in the sunitinib arm in the ITT patient population, 25% versus 9% in the intermediate- and poor-risk patients, and 13% compared to 11% in the favorable-risk patients. Importantly, at 96 months, 48% of patients in the nivo-ipi responders remained in response compared to just 19% in those who got sunitinib. And in the favorable-risk group, 36% of patients who responded remained in response, although data were not available for sunitinib in this subgroup.  So, this data reinforces the use of nivolumab and ipilimumab as a durable and effective first-line effective strategy for standard of care across all risk groups for advanced renal cell carcinoma. Dr. Neeraj Agarwal: Thank you, Jeanny. And of course, since ipi-nivo data were presented, several other novel ICI-TKI combinations have emerged. And I'm really hoping to see very similar data with TKI-ICI combinations down the line. It is really important to note that we are not seeing any new safety signals with the ICI combinations or ICI-based therapies, which is very reassuring given the extended exposure. Dr. Jeanny Aragon-Ching: Absolutely agree with you there, Neeraj.  Now, going on and moving on to Abstract 4514, which is the KEYNOTE-564 trial, and they reported on the 5-year outcomes of adjuvant pembrolizumab in clear cell RCC in patients who are at high risk for recurrence. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the KEYNOTE-564 trial established pembrolizumab monotherapy as the first adjuvant regimen to significantly improve both disease-free survival and overall survival compared to placebo after surgery for patients with clear cell renal cell carcinoma. So, Dr Naomi Haas presented the 5-year update from this landmark trial.  A total of 994 patients were randomized to receive either pembrolizumab or placebo. The median follow-up at the time of this analysis was approximately 70 months. Disease-free survival remained significantly improved with pembrolizumab. The median DFS was not reached with pembrolizumab compared to 68.3 months with placebo, with a hazard ratio of 0.71, translating to a 29% reduction in risk of recurrence. At 5 years, 60.9% of patients receiving pembrolizumab remained disease-free compared to 52.2% with placebo. Overall survival also favored pembrolizumab. The hazard ratio for OS was 0.66, translating to a 34% reduction in risk of death, with an estimated 5-year overall survival rate of 87.7% with pembrolizumab compared to 82.3% for placebo. Importantly, these benefits were consistent across all key subgroups, including patients with sarcomatoid features. In addition, no new serious treatment-related adverse events have been reported in the 3 years since treatment completion.  So, these long-term data confirm pembrolizumab as a durable and effective standard adjuvant therapy for patients with resected, high-risk clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Thank you for that wonderful summary, Neeraj. Dr. Neeraj Agarwal: That wraps up our kidney cancer highlights. Any closing thoughts, Jeanny, before we conclude? Dr. Jeanny Aragon-Ching: It's been so wonderful reviewing these abstracts with you, Neeraj. So, the 2025 ASCO Annual Meeting showcased a lot of transformative data across GU cancers, from first-in-class bispecifics to long-term survival in RCC. And these findings are already shaping our clinical practices. Dr. Neeraj Agarwal: I agree. And we have covered a broad spectrum of innovations in GU cancers with strong clinical relevance.  So, thank you, Jeanny, for joining me today and sharing your insights.  And thank you to our listeners for joining us. You will find links to the abstracts discussed today in the transcript of this episode. If you find these conversations valuable, please take a moment to rate, review, and subscribe to the ASCO Daily News Podcast wherever you listen. Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Neeraj Agarwal     @neerajaiims     Dr. Jeanny Aragon-Ching   Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,    Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics

Saavuttamattomien kansojen haaste on yhä kristikansan edessä. Miten Jeesuksen meille jättämään tehtävään voidaan vastata 2020-luvulla? Median välineitä hyödyntämällä lähetystyö on ottanut suuria harppauksia viimeisen kahdenkymmenen vuoden aikana ja tahti kiihtyy. Ohjelmassa vieraana Avainmedian toiminnanjohtaja Ilpo Jokimäki

Dr. Allison Zibelli and Dr. Rebecca Shatsky discuss advances in breast cancer research that were presented at the 2025 ASCO Annual Meeting, including a potential new standard of care for HER2+ breast cancer, the future of ER+ breast cancer management, and innovations in triple negative breast cancer therapy. Transcript Dr. Allison Zibelli: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Allison Zibelli, your guest host of the podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Comprehensive Cancer Center at Jefferson Health. There was a substantial amount of exciting breast cancer data presented at the 2025 ASCO Annual Meeting, and I'm delighted to be joined by Dr. Rebecca Shatsky today to discuss some of these key advancements. Dr. Shatsky is an associate professor of medicine at UC San Diego and the head of breast medical oncology at the UC San Diego Health Moores Cancer Center, where she also serves as the director of the Breast Cancer Clinical Trials Program and the Inflammatory and Triple-Negative Breast Cancer Program.  Our full disclosures are available in the transcript of this episode. Dr. Shatsky, it's great to have you on the podcast today. Dr. Rebecca Shatsky: Thanks, Dr. Zibelli. It's wonderful to be here. Dr. Allison Zibelli: So, we're starting with DESTINY-Breast09, which was trastuzumab deruxtecan and pertuzumab versus our more standard regimen of taxane, trastuzumab pertuzumab for first-line treatment of metastatic HER2-positive breast cancer. Could you tell us a little bit about the study? Dr. Rebecca Shatsky: Yeah, absolutely. So, this was a long-awaited study. When T-DXd, or trastuzumab deruxtecan, really hit the market, a lot of these DESTINY-Breast trials were started around the same time. Now, this was a global, randomized, phase 3 study presented by Dr. Sara Tolaney from the Dana-Farber Cancer Institute of Harvard in Boston. It was assessing essentially T-DXd in the first-line setting for metastatic HER2-positive breast cancer in addition to pertuzumab. And that was randomized against our standard-of-care regimen, which was established over a decade ago by the CLEOPATRA trial, and we've all been using that internationally for at least the past 10 years. So, this was a large trial, and it was one-to-one-to-one of patients getting T-DXd plus pertuzumab, T-DXd alone, or THP, which mostly is used as docetaxel and trastuzumab and pertuzumab every three weeks for six cycles. And this was in over 1,000 patients; it was 1,159 patients with metastatic HER2-positive breast cancer. This was a very interesting trial. It was looking at the use of trastuzumab deruxtecan, but patients were started on this treatment for their first-line metastatic HER2-positive breast cancer with no end date to their T-DXd. So, it was, you know, you were started on T-DXd every 3 weeks until progression. Now, CLEOPATRA is a little bit different than that, though, as we know. So, CLEOPATRA has a taxane plus trastuzumab and pertuzumab. But generally, patients drop the taxane after about six to seven cycles because, as we know, you can't be really on a taxane indefinitely. You get pretty substantial neuropathy as well as cytopenias, other things that end up happening. And so, in general, that regimen has sort of a limited time course for its chemotherapy portion, and the patients maintained after the taxane is dropped on their trastuzumab and their pertuzumab, plus or minus endocrine therapy if the investigator so desires. And the primary endpoint of the trial was progression-free survival by blinded, independent central review (BICR) in the intent-to-treat population. And then it had its other endpoints as overall survival, investigator-assessed progression-free survival, objective response rates, and duration of response, and of course, safety. As far as the results of this trial, so, I think that most of us key opinion leaders in breast oncology were expecting that this was going to be a positive trial. And it surely was. I mean, this is a really, really active drug, especially in HER2-positive disease, of course. So, the DESTINY-Breast03 data really established that, that this is a very effective treatment in HER2-positive metastatic breast cancer. And this trial really, again, showed that. So, there were 383 patients that ended up on the trastuzumab plus deruxtecan plus pertuzumab arm, and 387 got THP, the CLEOPATRA regimen. What was really interesting also to note of this before I go on to the results was that 52% of patients on this trial had de novo metastatic disease. And that's pretty unusual for any kind of metastatic breast cancer trial. It kind of shows you, though, just how aggressive this disease is, that a lot of patients, they present with de novo metastatic disease. It's also reflecting the global nature of this trial where maybe the screening efforts are a little bit less than maybe in the United States, and more patients are presenting as later stage because to have a metastatic breast cancer trial in the United States with 52% de novo metastatic disease doesn't usually happen. But regardless, the disease characteristics were pretty well matched between the two groups. 54% of the patients were triple positive, or you could say hormone-positive because whether they were PR positive or ER positive and PR negative doesn't really matter in this disease. And so, the interim data cutoff was February of this year, of 2025. So, the follow-up so far has been about 29 months, so the data is still really immature, only 38% mature for progression-free survival interim analysis. But what we saw is that T-DXd plus pertuzumab, it really improved progression-free survival. It had a hazard ratio that was pretty phenomenal at 0.56 with a confidence interval that was pretty narrow of 0.44 to 0.71. So, very highly statistically significant data here. The progression-free survival was consistent across all subgroups. Overall survival, very much immature at this time, but of course, the trend is towards an overall survival benefit for the T-DXd group. The median durable response with T-DXd plus pertuzumab exceeded 3 years. Now, importantly, though, I want to stress this, is grade 3 or above treatment-emergent adverse events occurred in both subgroups pretty equally. But there were 2 deaths in the T-DXd group due to interstitial lung disease. And there was a 12.1% adjudicated drug-induced interstitial lung disease/pneumonitis event rate in the T-DXd group and only 1%, and it was grade 1-2, in the THP group. So, that's really the caveat of this therapy, is we know that a percentage of patients are going to get interstitial lung disease, and that some may have very serious adverse events from it. So, that's always something I keep in the back of my mind when I treat patients with T-DXd. And so, overall, the conclusions of the trial were pretty much a slam dunk. T-DXd plus pertuzumab, it had a highly statistically significant and clinically meaningful improvement in progression-free survival versus the CLEOPATRA regimen. And that was across all subgroups for first-line metastatic HER2-positive breast cancer here. And so, yeah, the data was pretty impressive. Just to go into the overall response rate, because that's always super important as well, you had 85.1% of patients having a confirmed overall RECIST response rate in the T-DXd plus pertuzumab group and a 78.6 in the CLEOPATRA group. The complete CR rate, complete response was 15.1% in the T-DXd group and 8.5 in the CLEOPATRA regimen. And it was really an effective regimen in this group, of course. Dr. Allison Zibelli: So, the investigators say at the end of their abstract that this is the new standard of care. Would you agree with that statement? Dr. Rebecca Shatsky: Yeah, that was a bold statement to make because I would say in the United States, not necessarily at the moment because the quality of life here, you have to think really hard about. Because one thing that's really important about the DESTINY-Breast09 data is that this was very much an international trial, and in many of the countries where patients enrolled on this, they were not able to access T-DXd off trial. And so, for them, this means T-DXd now or potentially never. And so, that is a really big difference whereas internationally, that may mean standard of care. However, in the US, patients have no issues accessing T-DXd in the second- or third-line settings. And right now, it's the standard of care in the second line in the United States, with all patients basically getting this second-line therapy except for some unique patients where they may be doing a PATINA trial regimen, which we saw at San Antonio Breast Cancer in 2024 of the triple-positive patients getting hormonal therapy plus palbociclib, which had a really great durable response. That was super impressive as well. Or there is the patient that the investigator can pick KADCYLA because the patient really wants to preserve their hair or maybe it's more indolent disease. But the quality of life on T-DXd indefinitely in the first-line setting is a big deal because, again, that CLEOPATRA regimen allows patients to drop their chemotherapy component about five to six months in. And with this, you're on a drug that feels very chemo-heavy indefinitely. And so, I think there's a lot more to investigate as far as what we're going to do with this data in the United States because it's a lot to commit a patient in the first-line metastatic setting. These de novo metastatic patients, some of them may be cured, honestly, on the HER2-targeting regimen. That's something we see these days. Dr. Allison Zibelli: So, very interesting trial. I'm sure we'll be talking about this for a long time.  So, let's move on to SERENA-6, which was, I thought, a very interesting trial. This trial took patients with ER positive, advanced breast cancer after six months on an AI (aromatase inhibitor) and a CDK4/6 inhibitor. They did ctDNA every two to three months, and when they saw an ESR1 mutation emerge, they changed half of the patients to camizestrant plus CDK4/6 and kept the other half on the AI plus CDK4/6. Can you talk about that trial a little bit, please? Dr. Rebecca Shatsky: Yeah, so this was a big trial at ASCO25. This was presented as a Plenary Session. So, this was camizestrant plus a CDK4/6 inhibitor, and it could have been any of the three, so palbo, ribo, or abemaciclib in the first-line metastatic hormone-positive population, and patients were on an AI with that. They were, interestingly, tested by ctDNA at baseline to see if they had an ESR1 mutation. So, that was an interesting feature of this trial. But patients had to have already been on their CDK4/6 inhibitor plus AI for at least 6 months to enroll. And then, as you mentioned, they got ctDNA testing every 2 to 3 months. This was also a phase 3, double-blind, international trial. And I do want to highlight again, international here, because that's important when we're considering some of this data in the U.S. because it influences some of the results. So, this was presented by Dr. Nick Turner of the Royal Marsden in the UK. So, just a little bit of background for our listeners on ESR1 mutations and why they're important. This is the most common, basically, acquired resistance mutation to patients being treated with aromatase inhibitors. We know that treatment with aromatase inhibitors can induce this. It makes a conformational change in the estrogen receptor that makes the estrogen receptor constitutively active, which allows the cell to signal despite the influence of the aromatase inhibitor to decrease the estrogen production so that the ligand binding doesn't matter as much as far as the cell signaling and transcription is concerned. And camizestrant, you know, as an oral SERD, just to explain that a little bit too; these are estrogen receptor degraders. The first-in-class of a selective estrogen receptor degrader to make it to market was fulvestrant. And that's really been our standard-of-care estrogen degrader for the past 25 years, almost 25 years. And so, a lot of us are just looking for some of these oral SERDs to replace that. But regardless, they do tend to work in the ESR1-mutated population. And we know that patients on aromatase inhibitors, the estimates of patients developing an ESR1 mutation, depending on which study you look at, somewhere between 30% to 50% overall, patients will develop this mutation with hormone-positive metastatic breast cancer. There is a small percentage of patients that have these at baseline without even treatment of an aromatase inhibitor. The estimates of that are somewhere between 0.5 and up to 5%, depending on the trial you look at and the population. But regardless, there is a chance someone on their CDK4/6 inhibitor plus AI at 6 months' time course could have had an ESR1 mutation at that time. But anyway, so they got this ctDNA every 2 to 3 months, and once they were found to develop an ESR1 mutation, the patients were then switched to the oral SERD. AstraZeneca's version of the oral SERD is camizestrant, 75 mg daily. And then their type of CDK4/6 inhibitor was maintained, so they didn't switch the brand of their CDK4/6 inhibitor, importantly. And that was looked at then for progression-free survival, but these were patients with measurable disease by RECIST version 1.1. And the data cut off here was November of 2024. This was a big trial, you know, and I think that that's influential here because this was 3,256 patients, and that's a lot of patients. So, they were all eligible. And then 315 patients ended up being randomized to switch to camizestrant upon presence of that ESR1 mutation. So, that was 157 patients. And then the other half, so they were randomized 1:1, they continued on their AI without switching to an oral SERD. That was 158 patients. They were matched pretty well. And so, their baseline characteristics, you know, the two subgroups was good. But this was highly statistically significant data. I'm not going to diminish that in any way. Your hazard ratio was 0.44. Highly statistically significant confidence intervals. And you had a median progression-free survival in those that switched to camizestrant of 16 months, and then the non-switchers was 9.2 months. So, the progression-free survival benefit there was also consistent across the subgroups. And so, you had at 12 months, the PFS rate was 60.7% for the non-treatment group and 33.4% in the treatment group. What's interesting, though, is we don't have overall survival data. This is really immature, only 12% mature as far as overall survival. And again, because this was an international trial and patients in other countries right now do not have the access to oral SERDs that the United States does, the crossover rate, they were not allowed to crossover, and so, a very few patients, when we look at progression-free survival 2 and ultimately overall survival, were able to access an oral SERD in the off-trial here and in the non-treatment group. And so, that's really important as far as we look at these results. Adverse events were pretty minimal. These are very safe drugs, camizestrant and all the other oral SERDs. They have some mild toxicities. Camizestrant is known for something weird, which is called photopsia, which is some flashing lights in the periphery of the eye, but it doesn't seem to have any serious clinical significance that we know of. It has a little bit of bradycardia, but it's otherwise really well tolerated. You know, I hate to say that because that's very subjective, right? I'm not the one taking the drug. But it doesn't have any serious adverse events that would cause discontinuation. And that's really what we saw in the trial. The discontinuation rates were really low. But overall, I mean, this was a positive trial. SERENA-6 showed that switching to camizestrant at the first sign of an ESR1 mutation on CDK4/6 inhibitor plus AI improved progression-free survival. That's all we can really say from it right now. Dr. Allison Zibelli: So, let's move on to ASCENT-04, which was a bit more straightforward. Sacituzumab govitecan plus pembrolizumab versus chemotherapy plus pembrolizumab in PD-L1-positive, triple-negative breast cancer. Could you talk about that study? Dr. Rebecca Shatsky: Yeah, so this was also presented by the lovely Sara Tolaney from Dana-Farber. And this study made me really excited. And maybe that's because I'm a triple-negative breast cancer person. I mean, not to say that I don't treat hundreds of patients with hormone- positive, but our unmet needs in triple negative are huge because this is a disease where you have got to throw your best available therapy at it as soon as you can to improve survival because survival is so poor in this disease. The average survival with metastatic triple-negative breast cancer in the United States is still 13-18 months, and that's terrible. And so, for full disclosure, I did have this trial open at my site. I was one of the site PIs. I'm not the global PI of the study, obviously. So, what this study was was for patients who had had at least a progression-free survival of 6 months after their curative intent therapy or de novo metastatic disease. They were PD-L1 positive as assessed by the Dako 22C3 assay of greater than or equal to a CPS score of 10. So, that's what the KEYNOTE-355 trial was based on as well. So, standard definition of PD-L1 positive in breast cancer here. And basically, these patients were randomized 1:1 to either their sacituzumab govitecan plus pembrolizumab, day 1 they got both therapies, and then day 8 just the saci, as is standard for sacituzumab. And then the other group got the KEYNOTE-355 regimen. So, that is pembrolizumab with – your options are carbogem there, paclitaxel or nab-paclitaxel. And it's up to investigator's decision which upon those they decided. They followed these patients for disease progression or unacceptable toxicity. It was really an impressive trial in my opinion because we know already that this didn't just improve progression-free survival, because survival is so poor in this disease, of course, we know that it improved overall survival. It's trending towards that very much, and I think that's going to be shown immediately. And then the objective response rates were better, which is key in this disease because in the first-line setting, you've got a lot of people who, especially your relapsed TNBC that don't respond to anything. And you lose a ton of patients even in the first-line setting in this disease. And so, this was 222 patients to chemotherapy and pembro and 221 to sacituzumab plus pembro. Median follow-up has only been 14 months, so it's still super early here. Hazard ratio so far of progression-free survival is 0.65, highly statistically significant, narrow confidence intervals. And so, the median duration of response here for the saci group was 16.5 months versus 9.2 months. So, you're getting a 7-month progression-free survival benefit here, which in triple negative is pretty fantastic. I mean, this reminds me of when we saw the ASCENT data originally come out for sacituzumab, and we were all just so happy that we had this tool now that doubled progression-free and overall survival and made such a difference in this really horrible disease where patients do poorly. So, OS is technically immature here, but it's really trending very heavily towards improvement in overall survival. Importantly, the treatment-related adverse events in this, I mean, we know sacituzumab causes neutropenia, people who are experienced with this drug know how to manage it at this point. There wasn't any really unexpected treatment-related adverse events. You get some people with sacituzumab who have diarrhea. It's usually pretty manageable with some Imodium. So, it was cytopenias predominantly in this disease in this population that were highlighted as far as adverse events. But I'm going to be honest, like I was surprised that this wasn't the plenary over the SERENA-6 data because this, in my mind, there we have a practice-changing trial. I will immediately be trying to use this in my PD-L1 population because, to be honest, as a triple-negative breast cancer clinical specialist, when I get a patient with metastatic triple-negative breast cancer who's PD-L1 positive, I think, "Oh, thank God," because we know that part of the disease just does better in general. But now I have something that really could give them a durable response for much longer than I ever thought possible when I started really heavily treating this disease. And so, this was immediately practice-changing for me. Dr. Allison Zibelli: I think that it's pretty clear that this is at least an option, if not the option, for this group of patients. Dr. Rebecca Shatsky: Yeah, the duration of responses here was – it's just really important because, I mean, I do think this will make people live longer. Dr. Allison Zibelli: So, moving on to the final study that we're going to discuss today, neoCARHP (LBA500), which was neoadjuvant taxane plus trastuzumab, pertuzumab, plus or minus carbo(platin) in HER2-positive early breast cancer. I think this is a study a lot of us have been waiting for. What was the design and the results of this trial? Dr. Rebecca Shatsky: I was really excited about this as well because I'm one of those people that was waiting for this. This is a Chinese trial, so that is something to take note of. It wasn't an international trial, but it was a de-escalation trial which had become really popular in HER2-positive therapy because we know that we're overtreating HER2-positive breast cancer in a lot of patients. A lot of patients we're throwing the kitchen sink at it when maybe that is not necessary, and we can really de-escalate and try to personalize therapy a little bit better because these patients tend to do well. So, the standard of care, of course, in HER2-positive curative intent breast cancer with tumors that are greater than 2 cm is to give them the TCHP regimen, which is docetaxel, carboplatin, trastuzumab, and pertuzumab. And that was sort of established by several trials in the NeoSphere trial, and now it's been repeated in a lot of different studies as well. And so, that's really the standard of care that most people in the United States use for HER2-positive curative intent breast cancer. This was a trial to de-escalate the carboplatin, which I was super excited about because many of us who treat this disease a lot think carbo is the least important part of the therapy you're giving there. We don't really know that it's necessary. We've just been doing it for a long time, and we know that it adds a significant amount of toxicity. It causes thrombocytopenia, it causes severe nausea, really bad cytopenias that can be difficult in the last few cycles of this to manage. So, this trial was created. It randomized patients one to one with stage 2 and 3 HER2-positive breast cancer to either get THP, a taxane, pertuzumab, trastuzumab, similar to the what we do in first-line metastatic HER2-positive versus the whole TCHP with a carboplatin AUC of 6, which is what's pretty standard. And it was a non-inferiority trial, so important there. It wasn't to establish superiority of this regimen, which none of us, I think, were looking for it to. And it was a modified intent-to-treat population. And so, all patients got at least one cycle of this to be assessed as a standard for an intent-to-treat trial. And so, they assumed a pCR rate of about 62.8% for both groups. And, of course, it included both HER2-positive triple positives and ER negatives, which are, you know, a bit different diseases, to be honest, but we all kind of categorize them and treat them the same. And so, this trial was powered appropriately to detect a non-inferiority difference. And so, we had about 380 patients treated on both arms, and there was an absolute difference of only 1.8% of those treated with carbo versus those without. Which was fantastic because you really realized that de-escalation here may be something we can really do. And so, the patients who got, of course, the taxane regimen had fewer adverse events. They had way fewer grade 3 and 4 adverse events than the THP group. No treatment-associated deaths occur, which is pretty standard for- this is a pretty safe regimen, but it causes a lot of hospitalizations due to diarrhea, due to cytopenias, and neutropenic fever, of course. And so, I thought that this was something that I could potentially enact, you know, and be practice-changing. It's hard to say that when it's a trial that was only done in China, so it's not necessarily the United States population always. But I think for patients moving forward, especially those with, say, a 2.5 cm tumor, you know, node negative, those, I'd feel pretty comfortable not giving them the carboplatin here. Notes that I want to make about this population is that the majority were stage 2 and not stage 3. They weren't necessarily your inflammatory HER2-positive breast cancer patients. And that the taxane that was utilized in the trial is a little different than what we use in the United States. The patients were allowed to get nab-paclitaxel, which we don't have FDA approval for in the first-line curative intent setting for HER2-positive breast cancer in the United States. So, a lot of them got abraxane, and then they also got paclitaxel. We tend to use docetaxel every 3 weeks in the United States. So, just to point out that difference. We don't really know if that's important or not, but it's just a little bit different to the population we standardly treat. Dr. Allison Zibelli: So, are there patients that you would still give TCHP to? Dr. Rebecca Shatsky: Yeah, great question. I've been asked that a lot in the past like week since ASCO. I'd say in my inflammatory breast cancer patients, that's a group I do tend to sometimes throw the kitchen sink at. Now, I don't actually use AC in those because I know that that was the concern, but I think the TRAIN-2 trial really showed us you don't need to use Adriamycin in HER2-positive disease unless it's like refractory. So, I don't know that I would throw this on my stage 3C or inflammatory breast cancer patients yet because the majority of this were not stage 3. So, in your really highly lymph node positive patients, I'm a little bit hesitant to de-escalate them from the start. This is more of a like, if there's serious toxicity concerns, dropping carbo is absolutely fine here. Dr. Allison Zibelli: All right, great.  Thank you, Dr. Shatsky, for sharing your valuable insights with us on the ASCO Daily News Podcast today. Dr. Rebecca Shatsky: Thanks so much, Dr. Zibelli and ASCO Daily News. I really want to thank you for inviting me to talk about this today. It was really fun, and I hope you find my opinions on some of this valuable. And so, I just want to thank everybody and my listeners as well. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you like this podcast and you learn things from it, please take a moment to rate, review, and describe because it helps other people find us wherever you get your podcasts. Thank you again. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers Dr. Allison Zibelli Dr. Rebecca Shatsky @Dr_RShatsky Follow ASCO on social media:  @ASCO on Twitter  @ASCO on Bluesky  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. Allison Zibelli: No relationships to disclose Dr. Rebecca Shatsky: Consulting or Advisory Role: Stemline, Astra Zeneca, Endeavor BioMedicines, Lilly, Novartis, TEMPUS, Guardant Health, Daiichi Sankyo/Astra Zeneca, Pfizer Research Funding (Inst.): OBI Pharma, Astra Zeneca, Greenwich LifeSciences, Briacell, Gilead, OnKure, QuantumLeap Health, Stemline Therapeutics, Regor Therapeutics, Greenwich LifeSciences, Alterome Therapeutics  

Don tackles a stack of listener questions in this rapid-fire Friday Q&A, covering what a financial plan should cost, how tipping might work in a cashless future, and how to fine-tune a retirement portfolio with Avantis funds. He also addresses important estate planning steps after a death, how to use QCDs with inherited IRAs, and whether AUM fees are worth it compared to hourly planners. Along the way, he reflects on why he still manages his own money—and maybe shouldn't. 0:04 Intro to Friday Q&A and how listener questions are selected 2:12 What should a detailed retirement plan cost? Median price range explained 4:33 How will we tip in a cashless society? From bellboys to Bitcoin to Apple Pay 7:39 Listener portfolio check: 85% AVGE, 10% AVUV, 5% AVDV—too tilted? 11:36 Credit after death: Should an executor notify the credit bureaus? Yes—and how 13:45 Inherited IRA RMD workaround: Can QCDs help avoid taxes before age 70½? 17:02 AUM fees vs. flat-fee advisors: Is paying more for more assets fair? 25:51 Why Don still manages his own money (for now)—inertia, taxes, and habits Learn more about your ad choices. Visit megaphone.fm/adchoices

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Mathias ist Vorstandsvorsitzender von Axel Springer, Medienmanager, Autor und Journalist. Und vor allem ist er laut ChatGPT auf Platz 2 der mächtigsten Medienmänner weltweit. Ich wollte von ihm wissen, wie seine Biografie ihn geprägt hat, welche Werte er mit Freiheit verbindet und wie sich das eigene Verhältnis zu Geld verändert, wenn man Milliardär ist. Außerdem habe ich mich gefragt, was seine heutige Sicht auf den Fall Julian Reichelt ist. Wir sprechen über Macht, Vertrauen, Zweckpessimismus, es geht um Widerstand, Mut, Risiko, Diskussionskultur und familiäre Werte. WERBEPARTNER & RABATTE: https://linktr.ee/hotelmatze MEIN GAST: https://ullstein.de/urheberinnen/mathias-doepfner DINGE: Nile Rodgers - Le Freak: https://thalia.de/shop/home/artikeldetails/A1020984635 Benjamin von Stuckrad-Barre - Noch wach?: https://thalia.de/shop/home/artikeldetails/A1064678458 Maximilian Frisch - Produktion Torben Becker - Redaktion Lena Rocholl - Redaktion Mit Vergnügen - Vermarktung und Distribution MEIN ZEUG: Mein neues Fragenset: https://beherzt.net/liebe Mein neues Buch: https://bit.ly/3cDyQ18 Die Hotel Matze Suite bei Apple: https://apple.co/43V3hGq Die Hotel Matze Suite bei Spotify: https://spoti.fi/3U3ZySC Wunschgäste bitte in die Kommentare: https://apple.co/2RgJVH6 Mein Newsletter: https://matzehielscher.substack.com/ TikTok: https://tiktok.com/@matzehielscher Instagram: https://instagram.com/matzehielscher LinkedIn: https://linkedin.com/in/matzehielscher/ YouTube: https://bit.ly/2MXRILN Twitter: https://twitter.com/hotelmatze1 Mein erstes Buch: https://bit.ly/39FtHQy Mein erstes Fragenset: https://beherzt.net/matze

MDJ Script/ Top Stories for June 6th Publish Date:  June 6th    Commercial: From the BG AD Group Studio, Welcome to the Marietta Daily Journal Podcast.    Today is Friday, June 6th and Happy Birthday to Tommie Smith I’m Keith Ippolito and here are the stories Cobb is talking about, presented by Times Journal New $50,000 Median to Drive Safety on Fairground Street Attempted Carjacking Suspect Held at Gunpoint by Civilian, Arrested in Marietta Kennesaw’s Salute to America is July 3 Plus, Leah McGrath from Ingles Markets on controlling your sweet tooth All of this and more is coming up on the Marietta Daily Journal Podcast, and if you are looking for community news, we encourage you to listen and subscribe!  BREAK: TOP TECH MECHANICAL STORY 1: New $50,000 Median to Drive Safety on Fairground Street Marietta is enhancing road safety with a new median on Fairground Street near Haley Street. The $50,000 project, set to finish next week, aims to prevent U-turns that have caused accidents and traffic issues. The median will allow only left turns off Fairground Street, with 200 feet of median and 115 feet of curb being installed. Signage will alert drivers to the changes, ensuring smoother and safer traffic flow. STORY 2: Attempted Carjacking Suspect Held at Gunpoint by Civilian, Arrested in Marietta A carjacking suspect, Rico Riley, was arrested in Marietta after a witness, Gary Edwards, intervened and held him at gunpoint. Riley allegedly attempted to steal two cars at a Chevron gas station on Franklin Gateway. He first fought a woman for her car keys, then tried to carjack a second vehicle with a family inside. Edwards intervened both times, ultimately detaining Riley until police arrived. Riley faces multiple felony charges, including attempted armed robbery and child cruelty, and is held without bond. Marietta Police commend Edwards but urge witnesses to prioritize safety and call 911 in such situations. STORY 3: Kennesaw’s Salute to America is July 3 Kennesaw's annual Independence Day celebration, **Salute to America**, takes place July 3 from 6–10 p.m. in downtown Kennesaw. The free event features live music, food vendors, family activities, and a fireworks finale at 9:30 p.m. Performances include Tripp’n at 6 p.m., Girls Night Out at 7 p.m., and Guardians of the Jukebox at 8 p.m. Kids can enjoy ticketed inflatables, and food and drinks will be available for purchase. Reserved seating is $20, with reservations at kennesawjuly3.com. Tobacco and e-cigarettes are prohibited, and the event may be rescheduled for bad weather. We have opportunities for sponsors to get great engagement on these shows. Call 770.799.6810 for more info.  Break: Ingles Markets 2 STORY 4: Update: Asylum Seeker Married to Alpharetta Man Released on Bond Colombian asylum seeker Daniela Landin, 24, was released on a $10,000 bond after nearly a month in ICE custody. Married to Alpharetta resident Richard Landin, she fled gang violence in Colombia and sought asylum last year, though her initial request was denied and is under appeal. ICE detained her in May, citing an issue with her ankle monitor, despite it functioning properly. Her bond was granted after a delayed hearing, with the judge convinced of her sincerity and low flight risk. The couple, unable to fly due to her lack of ID, is driving back to Georgia, relieved to reunite. STORY 5: OUT AND ABOUT: 5 Things to Do This Weekend in Cobb County — June 6 - 8 This weekend in Cobb County offers a variety of events: Marietta Square hosts its free Art Walk Friday from 5-9 p.m., showcasing local art alongside shopping and dining. The BLADE Show at Cobb Galleria Centre runs Friday-Sunday, featuring unique blades and collectibles, with tickets starting at $30. The Kennesaw Grand Prix 5K kicks off Saturday at 8 a.m., followed by a post-race party. The Strand Theatre presents "Grease" with showtimes through June 22, and Swift-Cantrell Park in Kennesaw screens "Moana 2" Saturday at 8:15 p.m., with pre-movie activities starting at 6 p.m. Break: And now here is Leah McGrath from Ingles Markets on controlling your sweet tooth We’ll have closing comments after this. Break: TIDWELL TREES Signoff-   Thanks again for hanging out with us on today’s Marietta Daily Journal Podcast. If you enjoy these shows, we encourage you to check out our other offerings, like the Cherokee Tribune Ledger Podcast, the Marietta Daily Journal, or the Community Podcast for Rockdale Newton and Morgan Counties. Read more about all our stories and get other great content at mdjonline.com Did you know over 50% of Americans listen to podcasts weekly? Giving you important news about our community and telling great stories are what we do. Make sure you join us for our next episode and be sure to share this podcast on social media with your friends and family. Add us to your Alexa Flash Briefing or your Google Home Briefing and be sure to like, follow, and subscribe wherever you get your podcasts. Produced by the BG Podcast Network Show Sponsors: www.ingles-markets.com tidwelltrees.com toptechmech.com #NewsPodcast #CurrentEvents #TopHeadlines #BreakingNews #PodcastDiscussion #PodcastNews #InDepthAnalysis #NewsAnalysis #PodcastTrending #WorldNews #LocalNews #GlobalNews #PodcastInsights #NewsBrief #PodcastUpdate #NewsRoundup #WeeklyNews #DailyNews #PodcastInterviews #HotTopics #PodcastOpinions #InvestigativeJournalism #BehindTheHeadlines #PodcastMedia #NewsStories #PodcastReports #JournalismMatters #PodcastPerspectives #NewsCommentary #PodcastListeners #NewsPodcastCommunity #NewsSource #PodcastCuration #WorldAffairs #PodcastUpdates #AudioNews #PodcastJournalism #EmergingStories #NewsFlash #PodcastConversations See omnystudio.com/listener for privacy information.

Median house prices hit $1 million across capital cities, government taxes blamed for reigniting Australia’s tobacco wars. Plus, Erin Patterson takes the stand in her mushroom poisoning murder trial.See omnystudio.com/listener for privacy information.

This week in Canadian real estate, we saw a rare move toward improving housing affordability—but is it too little, too late?The federal government has announced a GST rebate for first-time home buyers purchasing new homes valued up to $1.5 million. Homes under $1 million will be eligible for a full GST rebate—as much as $50,000—while homes between $1 million and $1.5 million receive a partial rebate. The government claims this will help reduce upfront costs for young Canadians and spur new housing construction. But when you consider that only 10–20% of Canada's roughly 300,000 annual first-time buyers purchase new homes, this measure will actually benefit just 30,000 to 60,000 people nationwide. A step in the right direction? Yes. A scalable solution to affordability? Probably not.And while tax relief is welcome, the bigger issue continues to loom: the soaring cost of construction. Since 2017, Canada's Building Construction Price Index has jumped 90%, nearly doubling costs in just eight years—largely driven by pandemic-era supply chain shocks and inflation. This means even with incentives, developers are unlikely to hit federal housing targets, and pre-sale markets will remain fragile as margins thin and feasibility erodes.We also take a deep dive into Canada's residential mortgage debt, which now totals over $2.42 trillion—including $2.07 trillion in mortgages and $350 billion in HELOCs. That's nearly $370,000 in average mortgage debt across the 6.5 million homes with outstanding loans. With an average amortization of 20 years and today's fixed rates around 4.14%, the average monthly mortgage payment comes in at $2,256. That's barely more than Canada's average rent of $2,109, showing how thin the line between renting and owning has become for many households.Meanwhile in the U.S., delinquency rates on car loans have hit record highs—over 6.5% of borrowers are now more than 60 days behind. It's a stark indicator of mounting financial stress, and one that could spill over into the broader economy, potentially triggering interest rate cuts and even recessionary pressure stateside. A U.S. slowdown almost always influences Canada, especially when it comes to monetary policy.We also zoom out and look at G7 home price trends, and the results are jaw-dropping. Since 1985, Canada leads the G7 in inflation-adjusted home price appreciation—up 360%. That's even after an 18% national correction from peak pricing. For comparison, the UK is up 340%, the U.S. 220%, while Japan's prices have actually fallen 30%. The data paints a picture of just how extreme Canada's housing market has become over time—and how hard it may be to “normalize.”And finally, we preview next week's Bank of Canada interest rate decision. As of May 26th, odds are now sitting at 70% that there will be no cut, despite growing calls for relief. With inflation data holding steady and economic signals mixed, the BoC remains cautious.In our mini market update: Vancouver has just crossed 18,000 active listings—the most in 12 years—while May sales are on track to be the lowest ever recorded for the month, even as prices spike. Median prices are now within 1% of all-time highs, and average prices are up over $50,000 in just 30 days. It's a paradoxical moment: high supply, low sales, rising prices. Welcome to 2025. _________________________________ Contact Us To Book Your Private Consultation:

Pack your bags! The Median home sales prices in Logan, Utah dropped 5.8% year to $410,900. Russel Faucett, Owner of the Stern of Omada Real Estate joins the show to explain what is happening in Logan to make home prices a more affordable option.

Téměř všichni Češi chtějí, aby škola děti připravila na výzvy budoucnosti a naučila je kritickému myšlení, uvádí průzkum agentury Median pro Radiožurnál a Český rozhlas Plus. Jak připravit děti na měnící se svět? „Bylo by lepší, kdybychom se vrátili k jednotným osnovám a měli více pod kontrolou, co se ve školách vyučuje. Rámcové vzdělávací programy jsou nekoncepční a dávají možnost zasahovat do výuky třeba různým neziskovým organizacím,“ říká Petra Prokšanová (Stačilo!).

Češi považují za nejvážnější problém českého školství nedostatečné kapacity mateřských škol. V průzkumu agentury Median pro Radiožurnál a Český rozhlas Plus se na tom shodlo začátkem května přes 80 procent z 1000 respondentů. Co by s tím udělali politici? „Není to o tom, že by se nestavělo. Pomohla by větší koordinace obcí, které jsou ve své bezprostřední blízkosti. Stálo by za to i odbourat byrokracii, aby mohly vznikat dětské skupiny,“ říká Matěj Gregor (Motoristé sobě).

Posloucháte rádi Ptám se já? I letos pro nás i další pořady z dílny Seznam Zpráv můžete hlasovat v anketě Podcast roku. Moc děkujeme za podporu a přejeme příjemný poslech této epizody. --Motoristé sobě, největší překvapení loňských eurovoleb, by rádi zopakovali svůj úspěch i ve volbách do Sněmovny. Na voliče zafungoval fenomén jejich hlavní tváře Filipa Turka. Podle průzkumů ale strana ztrácí. Jak chce otočit trend? Hostem Ptám se já byl předseda strany Motoristé sobě Petr Macinka. Motoristé tento týden vyjíždějí do regionů za voliči se svou tour s názvem Opravíme stát. Podle lídra Petra Macinky je třeba opravit chyby napáchané dosavadními elitami, které způsobily, že motor se zadrhl. Strana například slibuje držet nízké výdaje státu a nezvyšovat daně nebo stavět se proti „ideologickým agendám“.Kampaň Motoristů podpoří i europoslanec, čestný předseda a hlavní tvář strany Filip Turek. Ten pravidelně vyvolává kontroverze, nedávno například svou příliš rychlou jízdou. Média teď navíc zpochybnila jeho pověst závodníka. Zda bude sám Turek do Poslanecké sněmovny kandidovat, ještě neoznámil. Narozdíl od loňských evropských voleb, kdy strana ve spolupráci s hnutím Přísaha získala dva mandáty, půjde do sněmovních voleb samostatně. Její ambicí je podle Macinky stát se součástí příští vládní koalice. Podle posledního volebního modelu agentury Median by se Motoristé do dolní komory parlamentu dostali a dokonce zaznamenali růst ze šesti sedm procent. Průzkumy dalších agentur ale ukazují spíše na opačný trend. Podle STEM Motoristům klesla podpora na 3,6 procenta. Na potřebnou pětiprocentní hranici pro vstup do Sněmovny by nedosáhli ani podle dat NMS. Jak chtějí Motoristé opravit Česko? Na koho chtějí v kampani mířit? A proč Filip Turek váhá s oznámením, zda bude kandidovat? --Podcast Ptám se já. Rozhovory s lidmi, kteří mají vliv, odpovědnost, informace.Sledujte na Seznam Zprávách, poslouchejte na Podcasty.cz a ve všech podcastových aplikacích.Archiv všech dílů najdete tady. Své postřehy, připomínky nebo tipy nám pište prostřednictvím sociálních sítí pod hashtagem #ptamseja nebo na e-mail: audio@sz.cz.

Welcome to the latest Bay Area Housing Market Update for May 2025!

Welcome to The Gwart Show! Today, Ethereum bull Ryan Berckmans joins us to dissect Ethereum's current strategy and why he believes it remains on the right path despite recent challenges. Ryan explains the "hub and spokes" L1+L2 model, arguing that communication failures—not technical problems—damaged ETH sentiment. He breaks down why L2 growth combined with L1 scaling will drive Ethereum toward becoming a multi-trillion dollar asset, how blob fees will generate significant revenue, and why Solana's success doesn't threaten Ethereum's long-term dominance in the institutional market. Subscribe to the newsletter! https://newsletter.blockspacemedia.com # Notes: • L2s like Base hit 100M+ in Bitcoin-backed loans • World L2 has 12M verified humans with 25M accounts • Ethereum plans to scale to 48 blobs per block • Current blob usage at ~80% full (2.4 per block) • Rollups may pay ~30% of revenue for blob space • Median user fees could remain at ~$0.01 with scale Timestamps: 00:00 Start 00:22 Who is Ryan B? 01:12 Why bullish on ETH? 06:38 Failure to communicate 11:01 Is this a pivot? 18:32 Justin Drake is bad at PR 24:31 Lido 28:05 Solo staking 31:50 It's all SOL's fault 33:03 Vitalik changing narratives 35:14 Thoughts on Solana 44:03 WHY NGU now? 48:50 Blobs need to pay up

Welcome to the "Saturday Morning Golf Stat" from the Hack it Out Golf Podcast. You've missed the green in the rough, but you're still hoping to get up and down and save a score. How far are you likely to end up from the hole when you're 35 yards away and in the rough? In this episode, Lou quizzes Mark and Greg on median distance by handicap. Afterwards, they reiterate why you need to be aware of what a good shot really is—and how expectation management can increase your performance on the course. Each of these will be a mini-episode (10-15 minutes long) about an interesting golf stat. We will discuss what you can learn, and most importantly, how you can apply this on the golf course to lower your scores and lower your handicap. Listen on your drive to the golf course or over your Saturday morning coffee! Data is sourced from Arccos Golf. They have over 1 BILLION shots in their database.  Check them out at: https://www.arccosgolf.com/  Use code DATALOU15 for 15% off! Learn more about your ad choices. Visit megaphone.fm/adchoices

Picking up from their previous discussion on the rise of million-dollar HDBs, George, Alfred, and Joan from PropertyLimBrothers return to discuss what buyers should watch for in 2025. They talked how current price trends—defined by ongoing cooling measures—are influencing buying power and long-term plans. Find out what they think about why prices in the OCR have surged, what's fuelling demand in the RCR, and how new launches are being priced island-wide.   Also, Joan shares why she believes it's better to act early, while Alfred outlines the logic behind starting with a two-bedder. They also touch on how to manage FOMO, read the shifts in policy, and stay grounded despite market noise. If you're trying to decide whether to buy, wait, or pivot—this episode offers clear, timely insight to help guide your next move.   00:00 Introduction 00:40 HDB price trend 03:09 Age always affects you 05:00 Interest rate will drop? 09:00 Future cooling measure scenario 12:22 Median age of buyers (New Private Home) 14:30 Advice for first time home owners 17:58 Median profit 18:30 Prices of private property market 25:42 RCR having more demand 28:30 Hottest new launches today 29:30 New Launch important things to take note 36:42 Upcoming New Launches 40:50 Closing 41:55 Outtakes

Host Dr. Davide Soldato and guest Dr. Harriet Kluger discuss the JCO article "Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Harriet Kluger. Dr. Kluger is a professor of medicine at Yale School of Medicine, Director of the Yale SPORE in Skin Cancer, and an internationally recognized expert in immuno-oncology for melanoma and renal cell carcinoma. She leads early-phase and translational trials that pair novel immunotherapies with predictive biomarkers to personalized care. Today, Dr. Kluger and I will be discussing the article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases." In this study, Dr. Kluger and colleagues evaluated four cycles of pembrolizumab plus the anti-VEGF antibody bevacizumab followed by pembrolizumab maintenance in patients with asymptomatic non-hemorrhagic melanoma brain metastases that had not previously received PD-1 therapy. Thank you for speaking with us, Dr. Kluger. Dr. Harriet Kluger Thank you for inviting me. The pleasure is really all mine. Dr. Davide Soldato So to kick off our podcast, I just wanted to ask if you could outline a little bit the biological and clinical rationale that led you to test this type of combination for patients with untreated brain metastases from metastatic melanoma. Dr. Harriet Kluger Back in approximately 2012, patients who had untreated brain metastases were excluded from all clinical trials. So by untreated, I mean brain metastases that had not received local therapy such as surgery or radiation. The reason for it was primarily because there was this fear that big molecules wouldn't penetrate brain lesions because they can't pass the blood-brain barrier. Turns out that the blood-brain barrier within a tumor is somewhat leaky and drugs sometimes can get in there. When PD-1 inhibitors were first identified as the next blockbuster class of drugs, we decided to conduct a phase 2 clinical trial of pembrolizumab monotherapy in patients with untreated brain metastases. We actually did it also in lung cancer, and we could talk about that later on. Responses were seen. The responses in the brain and the body were similar. They were concordant in melanoma patients. Now, at approximately that time, also another study was done by the Australian group by Dr. Georgina Long, where they did a randomized trial where patients who didn't require immediate steroid therapy received either nivolumab alone or nivolumab with ipilimumab, and the combination arm was substantially superior. Subsequently, also, Bristol Myers Squibb also conducted a large phase 2 multicenter trial of ipilimumab and nivolumab in patients with untreated brain metastases. And there, once again, they saw that the responses in the brain were similar to the responses in the body. Now, somewhere along the line there, we completed our anti-PD-1 monotherapy trial. And when we looked at our data, we still didn't have the data on ipilimumab and nivolumab. And our question was, “Well, how can we do better?” Just as we're always trying to do better. We saw two really big problems. One was that patients had a lot of perilesional edema. And the other one was that we were struggling with radiation necrosis in lesions that were previously Gamma Knifed. The instance of radiation necrosis was in excess of 30%. So the rationale behind this study was that if we added bevacizumab, maybe we could treat those patients who had some edema, not requiring steroids, but potentially get them on study, get that PD-1 inhibitor going, and also prevent subsequent radiation necrosis. And that was the main rationale behind the study. We had also done some preclinical work in mouse models of melanoma brain metastases and in an in vitro blood-brain barrier model where we showed that bevacizumab, or anti-VEGF, really tightens up those leaky basement membranes and therefore would be very likely to decrease the edema. Dr. Davide Soldato Thank you very much for putting in context the combination. So this was a phase 2 trial, and you included patients who had at least one lesion, and you wanted lesions that were behind 5 and 20 millimeters. Patients could be included also if the brain metastasis was higher in dimension than 20 millimeters, but it had to be treated, and it was then excluded from the evaluation of the primary objective of the trial. So regarding, a little bit, these characteristics, do you think that this is very similar to what we see in clinical practice? And what does this mean in terms of applicability of these results in clinical practice? Dr. Harriet Kluger So that's an excellent question. The brain metastasis clinical research field has somewhat been struggling with this issue of inclusion/exclusion criteria. When we started this, we showed pretty clearly that 5 to 10 millimeter lesions, which are below the RECIST criteria for inclusion, are measurable if you use MRIs with slices that are 1 to 2 millimeters. Most institutions in the United States do use these high-resolution MRIs. I don't know how applicable that is on a worldwide scale, but we certainly lowered the threshold for inclusion so that patients who have a smattering of small brain metastases would be eligible. Now, patients with single large brain metastases, the reason that we excluded those from the trial was because we were afraid that if a patient didn't respond to the systemic therapy that we were going to give them, they could really then develop severe neurological symptoms. So, for patient safety, we used 20 millimeters as the upper level for inclusion. Some of the other trials that I mentioned earlier also excluded patients with very large lesions. Now, in practice, one certainly can do Gamma Knife therapy to the large lesions and leave the smaller ones untreated. So I think it actually is very applicable to clinical practice. Dr. Davide Soldato Thank you very much for that insight, because I think that sometimes criteria for clinical trials, they have to be very restrictive. But then we know that in clinical practice, the applicability of these results is probably broader. So, going a little bit further in the results of the study, I just wanted a little bit of comment from you regarding what you saw in terms of intracranial response rate and duration of response among patients who obtained a response from the combination treatment. Dr. Harriet Kluger So we were actually surprised. When we first designed this study, as I said earlier, we weren't trying to beat out ipilimumab and nivolumab. We were really just trying to exclude those patients who wouldn't have otherwise been eligible for ipilimumab and nivolumab because of edema or possibly even previous radiation necrosis. So it was designed to differentiate between a response rate of 34%, and I believe the lower bound was somewhere in the 20s, because that's what we'd seen in the previous pembrolizumab study. What we saw in the first 20 patients that we enrolled was actually a response rate that far exceeded that. And so we enrolled another cohort to verify that result because we were concerned about premature publishing of a result that we might have achieved just by chance. The two cohorts were very similar in terms of the response rates. And certainly this still needs to be verified in a second study with additional institutions. We did include the Moffitt Cancer Center, and the response rate with Moffitt Cancer Center was very similar to the Yale Cancer Center response rate. Now, your other question was about duration of response. So the other thing that we started asking ourselves was whether this high response rate was really because the administration of the anti-VEGF will decrease the gadolinium enhancement and therefore we might actually just be seeing prettier scans but not tumor shrinkage. And the way to differentiate those two is by looking at the duration of the response. Median progression-free survival was 2.2 years. That's pretty long. The upper bound on the 95% confidence interval was not reached. I can't tell you that the duration is as good as the duration would be when you give ipilimumab. Perhaps it is less good. This was a fairly sick population of patients, and it included some who might not have been able to receive ipilimumab and nivolumab. So it provides an alternative. I do believe that we need to do a randomized trial where we compare it to ipilimumab and nivolumab, which is the current standard of care in this patient population. We do need to interpret these results with caution. I also want to point out regarding the progression-free survival that we only gave four doses of anti-VEGF. So one would think that even though anti-VEGF has a long half-life of three or four weeks, two years later, you no longer have anti-VEGF effect, presumably. So it does something when it's administered fairly early on in the course of the treatment. Dr. Davide Soldato So, in terms of clinical applicability, do you see this combination of pembrolizumab and bevacizumab - and of course, as we mentioned, this was a phase 2 trial. The number of patients included was not very high, but still you saw some very promising results when compared with the combination of ipilimumab and nivolumab. So do you see this combination as something that should be given particularly to those patients who might not be able to receive ipilimumab and nivolumab? So, for example, patients who are very symptomatic from the start or require a high dose of steroids, or also to provide a quicker response in terms of patients who have neurological symptoms, or do you think that someday it could be potentially used for all patients? Dr. Harriet Kluger The third part of your question, whether it can be used someday for all patients: I think we need to be very careful when we interpret these results. The study was substantially smaller than the ipilimumab/nivolumab trial that was conducted by Bristol Myers Squibb. Also going to point out that was a different population of patients. Those were all frontline patients. Here we had a mix of patients who'd had previous anti-CTLA-4 and frontline patients. So I don't think that we can replace ipilimumab and nivolumab with these results. But certainly the steroid-sparing aspect of it is something that we really need to take into consideration. A lot of patients have lesions in locations where edema can be dangerous, and some of them have a hard time coming off the steroids. So this is certainly a good approach for those folks. Dr. Davide Soldato And coming back to something that you mentioned in the very introduction, when you said that there were two main problems, which was one, the problem of the edema, and the second one, the problem of the radionecrosis. In your trial, there was a fair percentage of patients who received some type of local treatment before the systemic one. So the combination of pembrolizumab and bevacizumab. And most of the patients received radiosurgery. So I just wanted a brief comment regarding the incidence of radionecrosis in the trial and whether that specific component of the combination with bevacizumab was reduced. And how do you think that this fares in terms of what we see in clinical practice in terms of radionecrosis? Dr. Harriet Kluger I'm not sure that we really reduced the incidence of radiation necrosis. We saw radiation necrosis here. We saw less of it than in the trial of pembrolizumab monotherapy, but these were also different patients, different time. We saw more than we thought that we were going to see. It was 27%, I believe, which is fairly high still. We only gave the four doses of bevacizumab. Maybe to really prevent radiation necrosis, you have to continue to give the bevacizumab. That, too, needs to be tested. The reason that we gave the four doses of bevacizumab was simply because of the cost of the bevacizumab at the time. Dr. Davide Soldato Thank you very much for that comment on radionecrosis. And I really think that potentially this is a strategy, so continuing the bevacizumab, that really makes a lot of sense, especially considering that the tolerability of the regimen was really very, very good, and you didn't see any significant or serious adverse events related to bevacizumab. So just wondering if you could comment a little bit on the toxicities, whether you had anything unexpected. Dr. Harriet Kluger There was one patient who had a microperforation of a diverticulum, which was probably related to the bevacizumab. It was conservatively managed, and the patient did fine and actually remains alive now, many years later. We had one patient who had dehiscence of a previous wound. So there is some. We did not see any substantial hypertension, proteinuria, but we only gave the four doses. So it is possible that if you give it for longer, we would see some side effects. But still, relative to ipilimumab, it's very, very well tolerated. Dr. Davide Soldato Yeah, exactly. I think that the safety profile is really different when we compare the combination of ipilimumab/nivolumab with the pembrolizumab/bevacizumab. And as you said, this was a very small trial and probably we need additional results. But still, these results, in terms of tolerability and safety, I think they are very interesting. So one additional question that I think warrants a little bit of comment on your part is actually related to the presence of patients with BRAF mutation and, in general, to what you think would be the best course of treatment for these patients who present with the upfront brain metastases. So this, it's actually not completely related to the study, but I think that since patients with BRAF mutation were included, I think that this warrants a little bit of discussion on your part. Dr. Harriet Kluger So we really believe that long-term disease control, particularly in brain metastases, doesn't happen when you give BRAF/MEK inhibitors. You sometimes get long-term control if you've got oligometastatic disease in extracranial sites and if they've previously been treated with a lot of immune checkpoint inhibitors, which wasn't the case over here. So a patient who presents early in the course of the disease, regardless of their BRAF status, I do believe that between our studies and all the studies that have been done on immunotherapy earlier in the course of disease, we should withhold BRAF/MEK inhibitors unless they have overwhelming disease and we need immediate disease control, and then we switch them very quickly to immunotherapy. Can I also say something about the toxicity question from the bevacizumab? I have one more comment to make. I think it's important. We were very careful not to include patients who had overt hemorrhage from brain metastases. So melanoma brain metastases relative to other tumor types tend to bleed, and that was an exclusion criteria. We didn't see any bleeding that was attributable to the bevacizumab, but we don't know for sure that, if this is widely used, that that might not be a problem that's observed. So I would advise folks to use extreme caution and perhaps not use it outside of the setting of a clinical trial in patients with overt hemorrhage in the melanoma brain metastases. Dr. Davide Soldato Thank you very much. I think that one aspect that is really interesting in the trial is actually related to the fact that you collected a series of biomarkers, both circulating ones, but also some that were collected actually from the tissue. So just wondering if you could explain a little bit which type of biomarkers you evaluated and whether you saw any significant results that could suggest higher or lower efficacy of the combination. Dr. Harriet Kluger Thank you for that. So yes, the biomarker studies are fairly exploratory, and I want to emphasize that we don't have anything that's remotely useful in clinical practice at this juncture. But we did see an association between vessel density in the tumors and improved response to this regimen. So possibly those lesions that are more vascular are more fed by or driven by VEGF, and that could be the reason that there was improved response. We also saw that when there was less of an increase in circulating angiopoietin-2 levels, patients were more likely to respond. Whether or not that pans out in larger cohorts of patients remains to be determined. Dr. Davide Soldato Still, do you envision validation of these biomarkers in a potentially additional trial that will evaluate, again, the combination? Because I think that the signals were quite interesting, and they really make sense from a biological point of view, considering the mechanism of action of bevacizumab. So I think that, yeah, you're right, they are exploratory. But still, I think that there is very strong biological rationale. So really I wanted to congratulate you on including that specific part and on reporting it. And so the question is, really, do you envision validation of these biomarkers in larger cohorts? Dr. Harriet Kluger I would hope to see that, just as I'd like to see validation of the clinical results as well. The circulating biomarkers are very easy to do. It's a simple ELISA test. And the vessel density on the tumor is essentially CD34 staining and units per area of tumor. Also very simple to do. So I'd love to see that happen. Dr. Davide Soldato Do you think that considering the quality of the MRI that we are using right now, it would be possible to completely bypass even the evaluation on the tissue? Like, are we going in a direction where we can, at a certain point, say the amount of vessels that we see in these metastases is higher versus lower just based on MRI results? Dr. Harriet Kluger You gave me an outstanding idea for a follow-up study. I don't know whether you can measure the intensity of gadolinium as a surrogate, but certainly something worth asking our neuroradiology colleagues. Excellent idea. Thank you. Dr. Davide Soldato You're welcome. So just moving a step further, we spoke a lot about the validation of these results and the combination. And just wanted your idea on what do you think it would be more interesting to do: if designing a clinical trial that really compares pembrolizumab/bevacizumab with ipilimumab and nivolumab or going directly for the triplet. So we know that there has been some type of exploration of triplet combination in metastatic melanoma. So just your clinical impression: What would you do as an investigator? Dr. Harriet Kluger So it's under some discussion, actually. It's very difficult to compare drugs from different companies in an investigator-initiated trial. Perhaps our European colleagues can do that trial for us. In the United States, it's much harder, but it can be done through the cooperative groups, and we are actually having some discussions about that. I don't have the answer for you. It would be lovely to have a trial that compared the three drugs to ipi/nivo and to pembrolizumab/bevacizumab. So a three-arm trial. But remember, these are frontline melanoma patients. There aren't that many of them anymore like there used to be. So accrual will be hard, and we have to be practical. Dr. Davide Soldato Yeah, you're right. And in the discussion of the manuscript, you actually mentioned some other trials that are ongoing, especially one that is investigating the combination of pembro and lenvatinib, another one that is investigating the combination of nivolumab and relatlimab. So just wondering, do you think that the molecule in terms of VEGF inhibition, so bevacizumab versus lenvatinib, can really make a difference or is going to be just a mechanism of action? Of course, we don't have the results from this trial but just wondering if you could give us a general comment or your opinion on the topic. Dr. Harriet Kluger So that's a really great question. The trial of pembrolizumab and lenvatinib was our answer to the fact that bevacizumab is not manufactured by the same company as pembrolizumab, and we're trying to give a practical answer to our next study that might enable us to take this approach further. But it does turn out from our preclinical studies that bevacizumab and VEGF receptor inhibition aren't actually the same thing in terms of the effects on the blood-brain barrier or the perilesional tumor microenvironment in the brain. And these studies were done in mice and in in vitro models. Very different effects. The lenvatinib has stronger effect on the tumors themselves, the tumor cells themselves, than the bevacizumab, which has no effect whatsoever. But the lenvatinib doesn't appear to tighten up that blood-brain barrier. Dr. Davide Soldato Thank you. I think that's very interesting, and I think it's going to be interesting to see also results of these trials to actually improve and give more options to our patients in terms of different mechanism of action, different side effects. Because in the end, one thing that we discussed is that some combination may be useful in some specific clinical situation while others cannot be applicable, like, for example, an all immunotherapy-based combination. Just one final comment, because I think that we focused a lot on the intracranial response and progression-free survival. You briefly mentioned this but just wanted to reinforce the concept. Did you see any differences in terms of intracranial versus extracranial response for those patients who also had extracranial disease with the combination of pembro and bevacizumab? Dr. Harriet Kluger So the responses were almost always concordant. There were a couple of cases that might have had a body response and not an intracranial response and vice-versa, but the vast majority had concordant response or progression. We do believe that it's a biological phenomenon. The type of tumor that tends to go to the brain is going to be the type of tumor that will respond to whatever the regimen is that we're giving. In the previous trial also, we saw concordance of responses in the body and the brain. Dr. Davide Soldato Thank you very much. Just to highlight that really the combination is worth pursuing considering that there was not so much discordant responses, and the results, even in a phase 2 trial, were very, very promising. So thank you again, Dr. Kluger, for joining us today and giving us a little bit of insight into this very interesting trial. Dr. Harriet Kluger Thank you for having me. Dr. Davide Soldato So we appreciate you sharing more on your JCO article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases," which gave us the opportunity to discuss current treatment landscape in metastatic melanoma and future direction in research for melanoma brain metastasis. If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

When is the right time to buy a home? For many, it's when they feel ready—personally and financially. But even then, timing the market, understanding future price direction, and interpreting shifting economic signals can complicate the decision. In this episode, we break down everything you need to know to make a confident, informed choice about buying a home in 2025.First, we examine the all-powerful & predominant force of interest rates. The Bank of Canada held steady in April, but with two more rate cuts expected in June and September, we could see the overnight rate drop to 2.25% by year-end. Variable-rate holders may feel relief by the fall, while fixed rates have remained mostly unchanged—making the 3.99% offers available now historically attractive, even if there's potential for further dips.But rates don't act alone. Sentiment plays a massive role. Despite consumer confidence hitting all-time lows, April brought a slight rebound—too soon to call it a trend. However, business sentiment continues to deteriorate, dragging down the Real Estate Outlook Index at its fastest pace since the 2022 rate shock. Sales volumes remain sluggish, and we don't expect a sharp bounce anytime soon.Real estate moves in cycles, and Vancouver's decades-long climb may be entering a slower phase. We revisit Toronto's 1989 peak, when prices fell 27% over seven years and took 22 years to recover in inflation-adjusted dollars. Could Vancouver follow a similar path after peaking in 2022? If so, prices may not reach those highs again until 2028 or later. Buying today means thinking long-term—and accepting that appreciation might not arrive on your timeline.Meanwhile, first-time buyers are getting older. In Canada, the average is now 33—up from 32 in the early '80s—while in Ontario it's hit 40. Surprisingly, Americans, with cheaper homes but more student debt, wait even longer (age 38 on average). What's driving Canadians to buy sooner? But supply is failing to keep up. March housing starts missed expectations by 14%, and condo construction is in freefall—down 45% from last year. Remove purpose-built rentals, and we're at 15-year lows. Ontario and BC, the provinces with the greatest need, are down 38% and 30% year-over-year. CMHC says we need 3.1 million more homes by 2030. At this rate, that's a pipe dream.On top of that, inventory levels are rising, especially in the pre-sale market. Vancouver could hit 3,500 unsold new condos by year-end—a 60% surge. With investor demand almost vanished (down from 50%, then 25% and now 7%!), developers are cancelling projects, and hundreds of homes won't break ground. Even with record immigration—Toronto just became North America's fastest-growing city—new supply is evaporating.We close with a mini-market update: May sales in Vancouver are trending at a six-year low (outside of COVID lockdowns), while inventory is at an 11-year high. Median prices are up slightly, but average prices are slipping. Could this be the inflection point?So… is now the right time to buy? That depends on your goals, your timeline, and your outlook. This episode delivers the data, trends, and insights to help you decide—with eyes wide open.Are you prepared to buy with the long-term in mind, even if prices don't rise during your ownership? Let's chat about it. _________________________________ Contact Us To Book Your Private Consultation:

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Spokojení s životem ve svém regionu jsou čtyři z pěti Čechů, ukázal exkluzivní průzkum agentury MEDIAN pro Radiožurnál a ČRo Plus. Nejspokojenější jsou obyvatelé Vysočiny a jihu ČR, zato na severu Čech, provázaném s útlumem těžby a navazujícího průmyslu, jen každý třetí z pěti. Horší nabídku pracovních pozic pociťují také obyvatelé u hranic jednotlivých krajů. Jakou zkušenost mají politici s dotačními programy pro rozvoj zaostávajících regionů? A co různé kraje potřebují?

Spokojení s životem ve svém regionu jsou čtyři z pěti Čechů, ukázal exkluzivní průzkum agentury MEDIAN pro Radiožurnál a ČRo Plus. Nejspokojenější jsou obyvatelé Vysočiny a jihu ČR, zato na severu Čech, provázaného s útlumem těžby a navazujícího průmyslu, jen každý třetí z pěti. Horší nabídku pracovních pozic pociťují také obyvatelé u hranic jednotlivých krajů. Jakou zkušenost mají politici s dotačními programy pro rozvoj zaostávajících regionů? A co různé kraje potřebují?

In a new report from the Kem C. Gardner Policy Institute showed that Utah's median income is ranked high among other states and middle-income households are earning more on average. Despite this, Utahns are still feeling the pinch of rising prices. Phil Dean, Chief Economist from the Kem C. Gardner Institute joins the show to discuss these findings and if these numbers really matter to the average Utahn.

Send us a textThis week, Teko & McFlei break down Jae Tips' Jazz 9 release rollout, sharing their thoughts on how the weekend played out and the energy behind the drop. The fellas also talk about JD Sports' ultra-limited release of the Air Max 95 Neon "Big Bubble", which hit select shelves overseas and left U.S. fans watching from afar.Patta is stirring the pot again, with leaked images of the upcoming Neon Air Max 90 "Waves" creating buzz ahead of the official drop. The guys also tap into the growing conversation around tariffs and what they could mean for sneaker consumers moving forward.All this and much more on this week's episode of The Sneaker Dads Podcast!Support the show

What will the impact be now that the U.S. has one of the highest tariff rates in the world?Topics covered include:Why the Trump administration raised tariffsHow the last round of U.S. tariffs led to higher prices and lower economic growthFour ways the world remains close to record connectivityWho have been the winners and losers from global tradeWhat will be the impact of this trade warEpisode SponsorsDelete Me – Use code David20 to get 20% offInsiders Guide Email NewsletterGet our free Investors' Checklist when you sign up for the free Money for the Rest of Us email newsletterOur Premium ProductsAsset CampMoney for the Rest of Us PlusShow NotesThe economic consequences of Mr Trump – looking for clarity in the tariffs chaos by Neil Shearing—Capital EconomicsTariff rate, most favored nation, simple mean, all products (%)—World Bank GroupDonald Trump's tariffs will fix a broken system by Peter Navarro—The Financial TimesDHL Global Connectedness Tracker—DHLObjective Knowledge: An Evolutionary Approach by Karl R. Popper—Oxford University PressGDP per capita (constant 2015 US$)—World Bank GroupJOSEPH E. STIGLITZ, GLOBALIZATION AND ITS DISCONTENTS REVISITED: ANTI-GLOBALIZATION IN THE ERA OF TRUMP, NEW YORK: W.W. NORTON & COMPANY, 2018 by Lino Sau—Annals of the Fondazione Luigi EinaudiFIFTY YEARS OF GROWTH IN AMERICAN CONSUMPTION, INCOME, ANDWAGES by Bruce Sacerdote—National Bureau of Economic ResearchReal Median Household Income in the United States—FREDEmployed full time: Median usual weekly real earnings: Wage and salary workers: 16 years and over—FREDConsumer Price Index for All Urban Consumers: Food in U.S. City Average/Median Household Income in the United States—FREDTrump's Love for Tariffs Began in Japan's '80s Boom By Jim Tankersley and Mark Landler—The New York TimesRelated Episodes515: Tariffs and the Mar-a-Lago Accord: What Trump Really Wants516: What Trump Wants Part 2 – How Trade Deficits and Capital Flows Can Harm or Help Countries427: Did the Tariffs Work? The Trade War Five Years Later212: Trade Wars Increase Prices and PovertySee Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Send us a textWashington County's real estate market has shifted to a more balanced position with 4.82 months of inventory, representing a 22% increase from last year, though slight downward pressure on pricing has resulted in only a 2% decrease in average sold prices.• Median sold price of $520,000 shows minimal change from last year at just 1.7% higher• Current 30-year fixed mortgage rate at 6.75%, down from 7.26% in January• Original list price to sold price ratio is 95.9%, indicating sellers are typically getting slightly less than asking• Days on market varies significantly by price point - homes between $400,000-$500,000 sell fastest at 51 days• Migration data shows buyers from areas with higher home values (California, Colorado) find Washington County prices reasonable• Housing market correlation with interest rates appears broken since 2022• Local economy shows greater diversity than pre-2008 recession when construction was 30% of economy• Current unemployment rate remains stable at around 3%Guest Branden DuCharme, CMT, Find Du Charme Wealth Management here:https://ducharmewealth.com/contact-us/Looking for a Real Estate expert? Find us here!https://realestate435.kw.com/www.wealth435.com https://linktr.ee/wealth435 Below are our wonderful friends!Find FS Coffee here:https://fscoffeecompany.com/Find Tuacahn Amphitheater here:https://www.tuacahn.org/Find Blue Form Media here:https://www.blueformmedia.com/#podcast #southernutah #investing #stgeorgeutah #realestate #435podcast #financialmarket #business #affordablehousing #afforadable [00:00:00] Intro.[00:00:48] Washington County Real Estate Overview.[00:08:33] Market Statistics and Current Trends.[00:18:32] Breaking Down Price Points and Days on Market.[00:27:46] The Conflict of Interest in Real Estate.[00:38:35] Home Value Comparisons Across States.[00:47:33] Employment Data and Economic Diversity.[00:57:46] Final Thoughts and Episode Wrap-Up.

How Is Living in Maine Different Than Visiting?Maine is one of the most beautiful states in the country—and if you've ever visited, you probably already know that. The rocky coastline, charming lobster shacks, peaceful lighthouses, and fresh ocean air make it an unforgettable vacation spot.But what's it really like to live in Maine?As a local Realtor who helps people Make Maine Your Home, I've had this conversation with countless clients—many of whom fell in love with Maine during a visit and are now wondering if they should make the leap.Spoiler alert: living in Maine is amazing, but it's a different experience from visiting. Here's what you need to know if you're considering the move.  1. The Pace of Life: Vacationland vs. RealityWhen you're here for a week, it's all about coastal drives, seafood feasts, and soaking in the scenery. But living here means experiencing the rhythm of Maine life—slower, more intentional, and deeply connected to nature.✅ Remote work is on the rise here—Maine had one of the highest rates in the country in 2023.✅ Life is peaceful, but expect longer drives for essentials, especially in rural areas.✅ Winters are no joke—think snow tires, plowing, and prepping for the power to go out!  2. Cost of Living: More Affordable Than You Think?Compared to neighboring states like Massachusetts or New Hampshire, Maine's real estate is surprisingly affordable.

The I Love CVille Show headlines: HUD Median Family Incomes Released Today CVille Area: $125,800 In 2025; $124,200 In 2024 Arlington/Alexandria/DC Area; $163,900 Median Anti-Tesla & Pro-Tesla Protests Saturday At Stonefield How Does UVA Rebuild Its Battered Brand? Charlottesville Business Brokers Has Cash Buyers R Odom Contract: $3.25M Base , 6 Yrs & Bonuses Joel Gardner, Chairman, Jefferson Council, (4/3) Read Viewer & Listener Comments Live On Air The I Love CVille Show airs live Monday – Friday from 12:30 pm – 1:30 pm on The I Love CVille Network. Watch and listen to The I Love CVille Show on Facebook, Instagram, Twitter, LinkedIn, iTunes, Apple Podcast, YouTube, Spotify, Fountain, Amazon Music, Audible, Rumble and iLoveCVille.com.

Home prices are falling fast in some prime real estate markets across the country while others remain stubbornly stuck. What's the defining factor between a stable housing market and one where sellers are actively cutting prices? Housing inventory! This metric defined the 2020 - 2022 run-up in home prices, but the rubber band of demand is snapping back as buyer power grows, housing inventory rises, and investors get even better buying opportunities. Remember when people said, “I'll buy when prices drop”? Well, now might be the time. ResiClub's Lance Lambert joins us to provide a holistic view of housing inventory, prices, demand, and emerging opportunities. Lance walks through the most up-to-date data on where housing inventory is rising fast, where prices are quickly declining, and which markets are holding on as sellers remain in control. We'll also talk about why homebuilding costs are about to JUMP and the reason Warren Buffett sold his homebuilding stocks shortly after buying them. Will construction slow down, limiting new inventory and leading us back into ultra-low supply? If so, this could push home prices higher, creating a prime opportunity for real estate investors. In This Episode We Cover US real estate markets seeing the most and least new inventory, and where prices are falling  Is spiking inventory a worrying sign for the housing market, or are we merely normalizing? What to look at in your housing market to forecast whether prices will rise or fall  Why are homebuilding costs about to JUMP, and could this lead to even more inventory problems? The new housing trend: Older renters, but could this mean more demand for rentals? And So Much More! Links from the Show Join the Future of Real Estate Investing with Fundrise Join BiggerPockets for FREE Sign Up for the On the Market Newsletter Find an Investor-Friendly Agent in Your Area Dave's BiggerPockets Profile ResiClub: The cost breakdown for constructing a single-family home in 2024 ResiClub: Did Warren Buffett see this coming? Homebuilder margins face pressure in 2025 ResiClub: The vanishing young homebuyer: Median first-time homebuyer age jumps from 28 in 1991 to 38 in 2024 Inventory Is Key to a Stable Real Estate Market—Will It Recover? Join Lance's Newsletter Grab Dave's Book, “Real Estate by the Numbers” Jump to topic: (0:00) Intro  (1:27) Hottest and Coldest Markets  (8:00) Should We Be Worried?  (11:00) Where Prices Are Dropping  (14:54) What to Look For In YOUR Market  (17:39) Homebuilding Costs To JUMP  (21:48) Developer Profits Shrink  (24:11) Older Renters, Better for Investors Check out more resources from this show on BiggerPockets.com and https://www.biggerpockets.com/blog/on-the-market-308 Interested in learning more about today's sponsors or becoming a BiggerPockets partner yourself? Email advertise@biggerpockets.com. Learn more about your ad choices. Visit megaphone.fm/adchoices

Cancer is one of the most terrifying illnesses of our age - a sudden change that happens silently inside our bodies and slowly eats away at us until there's nothing left. It's also one of the biggest failures of the pharmaceutical age - somewhere between 90 and 97% of all cancer drugs fail at clinical trials. Which is why we're unbelievably excited to bring you our conversation with Dr. Thomas Seyfried, Professor of Biology at Boston College who appears to be hot on the trail of a cure cancer that has nothing to do with the oncology-industrial-complex. According to the dozens of papers he and his colleagues have published over the last few decades, a strict ketogenic diet coupled to a glutamine inhibitor is sufficient to weaken cancer cells to the point that the immune system can actually clear the tumor. A recent paper from his group published in February of 2025 shows the stunning effects of his protocol in a small group of eighteen glioblastoma patients. Median survival for these patients for the last hundred years has been 12-15 months, but with Seyfried's intervention appears to have been extended up to 84 months. That's seven years, for those keeping score.We sit down with Seyfried to take apart his protocol, why it works for cancer, why no one's heard if it, and how everyone has completely misunderstood what cancer actually is.MAKE HISTORY WITH US THIS SUMMER:https://demystifysci.com/demysticon-2025PATREON https://www.patreon.com/c/demystifysciPARADIGM DRIFThttps://demystifysci.com/paradigm-drift-show(00:00) Go!(00:07:33) - Reception of Metabolic Cancer Research(00:10:05) - Breakthrough in Glioblastoma Treatment(00:14:49) - Glutamine-Glutamate Cycle in Cancer(00:16:33) - Challenges and Critiques of Standard Care(00:17:43) - Barriers to Implementing Metabolic Therapies(00:24:19) - Radiation and Cancer Treatment(00:26:07) - Metabolic Approach to Cancer(00:27:30) - Evolutionary Biology's Role in Understanding Cancer(00:28:52) - Mitochondria's Role in Cellular Destiny(00:31:39) - The Oxidative Phosphorylation Process(00:35:28) - Cancer and Mitochondrial Function(00:38:43) - Cellular Electrochemical Gradients(00:41:30) - Cancer's Dependency on Fermentable Fuels(00:45:08) - Glutamine's Role in Cancer Treatment(00:52:11) - Patient Compliance and Dietary Challenges(00:55:33) - Glucose Ketone Index for Health Monitoring(01:06:48) - Fenbendazole and Cancer Research(01:10:02) - Medical Industry Business Models(01:13:27) - Diets and Nutritional Ketosis(01:17:06) - Metabolic Variability and Personalization(01:19:25) - Exercise and Metabolic Health(01:23:43) - Historical Misconceptions in Cancer Treatment(01:26:21) - Obesity and Cancer Prevention(01:28:00) - Metabolic Theories of Cancer(01:47:18) - Metastatic Cancer Origins(01:55:24) - Therapeutic and Collaborative Approaches(01:59:57) - Practical Steps and Transformations#CancerResearch, #glioblastoma, #CancerAwareness, #Oncology, #CancerTreatment, #CancerSurvivor, #FightCancer, #EndCancer, #CancerSupport, #ClinicalTrials, #CancerWarrior, #BeatCancer, #CureCancer, #CancerFighter, #StayStrong, #CancerCommunity, #philosophypodcast, #sciencepodcast, #longformpodcast ABOUS US: Anastasia completed her PhD studying bioelectricity at Columbia University. When not talking to brilliant people or making movies, she spends her time painting, reading, and guiding backcountry excursions. Shilo also did his PhD at Columbia studying the elastic properties of molecular water. When he's not in the film studio, he's exploring sound in music. They are both freelance professors at various universities. SOCIAL: - Discord: https://discord.gg/MJzKT8CQub- Facebook: https://www.facebook.com/groups/DemystifySci- Instagram: https://www.instagram.com/DemystifySci/- Twitter: https://twitter.com/DemystifySciMUSIC: -Shilo Delay: https://g.co/kgs/oty671

Home prices are falling fast in some prime real estate markets across the country while others remain stubbornly stuck. What's the defining factor between a stable housing market and one where sellers are actively cutting prices? Housing inventory! This metric defined the 2020 - 2022 run-up in home prices, but the rubber band of demand is snapping back as buyer power grows, housing inventory rises, and investors get even better buying opportunities. Remember when people said, “I'll buy when prices drop”? Well, now might be the time. ResiClub's Lance Lambert joins us to provide a holistic view of housing inventory, prices, demand, and emerging opportunities. Lance walks through the most up-to-date data on where housing inventory is rising fast, where prices are quickly declining, and which markets are holding on as sellers remain in control. We'll also talk about why homebuilding costs are about to JUMP and the reason Warren Buffett sold his homebuilding stocks shortly after buying them. Will construction slow down, limiting new inventory and leading us back into ultra-low supply? If so, this could push home prices higher, creating a prime opportunity for real estate investors. In This Episode We Cover: Is spiking inventory a worrying sign for the housing market, or are we merely normalizing? What to look at in your housing market to forecast whether prices will rise or fall  Why are homebuilding costs about to JUMP, and could this lead to even more inventory problems? The new housing trend: Older renters, but could this mean more demand for rentals? And So Much More! Links from the Show Join BiggerPockets for FREE Let Us Know What You Thought of the Show! Ask Your Question on the BiggerPockets Forums BiggerPockets YouTube Apply to Be a BiggerPockets Real Estate Guest ResiClub: The cost breakdown for constructing a single-family home in 2024 ResiClub: Did Warren Buffett see this coming? Homebuilder margins face pressure in 2025 ResiClub: The vanishing young homebuyer: Median first-time homebuyer age jumps from 28 in 1991 to 38 in 2024 Invest in Private Market Real Estate with the Fundrise Flagship Fund Grab Dave's Book, “Real Estate by the Numbers” Sign Up for the BiggerPockets Real Estate Newsletter Find an Investor-Friendly Agent in Your Area Inventory Is Key to a Stable Real Estate Market—Will It Recover? Join Lance's Newsletter Connect with Dave Check out more resources from this show on BiggerPockets.com and https://www.biggerpockets.com/blog/real-estate-1101 Interested in learning more about today's sponsors or becoming a BiggerPockets partner yourself? Email advertise@biggerpockets.com. Learn more about your ad choices. Visit megaphone.fm/adchoices

The Bureau of Labor Statistics released data on the median salaries of Americans, revealing a significant gap between what people earn and what they feel is necessary to live comfortably. In this episode, Art shares his thoughts on the findings and offers tips for cultivating a content heart.Resources: 8 Money MilestonesAsk a Money Question!

In this episode of the Primal Potential Podcast, we're diving into three powerful but simple strategies to help you optimize your blood sugar, improve your insulin sensitivity, and increase your energy levels. These are real-world, easy-to-implement hacks that go beyond the usual “eat less sugar” advice. Before we get started, grab your copy of my new Fat Loss E-Book! Here's the link. And, head over to my new YouTube channel to subscribe and turn on notifications before the new Carb Series kicks off next week.  Hack #1: Get Sunlight First Thing in the Morning ☀️ Did you know that getting direct sunlight within the first hour of waking helps reset your circadian rhythm, which plays a major role in blood sugar regulation and insulin sensitivity? Pairing this with light movement (like a 10-minute walk or some gentle stretching) can improve how efficiently your body uses glucose before breakfast. What the Science Says: On average, exposure to sunlight improved insulin sensitivity by 18.75%. Median improvement was 18%, meaning half of people experienced even greater benefits. Range of effects: Sunlight exposure improved insulin function by 15-22%. Glucose tolerance: Participants who got more sunlight saw a 12-16% improvement in how well their bodies processed carbohydrates.

Today, as part of our “Tricks of the Trade” series, we’re at the Houston Livestock Show and Rodeo, where students put goats and lambs up for sale to the highest bidder. Here, livestock auctions generate a pile of philanthropic money for a Texas scholarship fund, and the bids go up and up and up. But first: Air travel is in a snarl today with a power outage at London’s Heathrow Airport.

Today, as part of our “Tricks of the Trade” series, we’re at the Houston Livestock Show and Rodeo, where students put goats and lambs up for sale to the highest bidder. Here, livestock auctions generate a pile of philanthropic money for a Texas scholarship fund, and the bids go up and up and up. But first: Air travel is in a snarl today with a power outage at London’s Heathrow Airport.

How do local Indianapolis Real Estate Investors compete in an increasingly competitive market? The Home Value growth in Indianapolis is 42% since 2020. The Median home price in 2020 was$170,000, but it has increased to $240,000. 2%-4% mortgage rates have risen to 8%.Many people are leaving bigger cities for more affordable living in Indiana. Large Out-of-State corporate investors are swooping in to grab up single-family homes and apartments. Competition for finding good real estate deals is increasingly hard to come by. It's like a gold rush in Indiana.But there is hope for success in Indy for wholesalers and other local investors. Partly, it does take a bit of extra work digging twice as hard as we've been used to. Some of us have gotten lazy, taking the easy deals for granted. But there are deals out there.Local investors and wholesalers have a lot of advantages compared to out-of-state buyers. Many out of state buyers have been developing bad reputations. This is where local investors with consistent track records and face to face encounters goes a long way.Out of State buyers may be able to offer more money, and sometimes that's what it comes down to. But local buyers can offer trust, as many sellers are getting burned by corporate conglomerates. And many out of state investors are coming for 6-12 months and then packing up and leaving. For those local buyers sticking around, consistency builds your credibility.It's not about making big adjustments for buyers right now. It's about make small ones. Maybe you can safely buy at a little higher ARV percentage than you used to be able. Maybe you need to attend more Meet-Ups and other events to make a few extra connections that get you that deal. Maybe you just need to have your ducks lined up better for financing to be a little bit quicker to get the deal when available, so you can close faster. Maybe it's exploring new areas that will be the next Fountain Square. Maybe doing delayed flips and continuing to rent for a few years is a successful recipe as properties appreciate.The moral of the story is, those investors who are in the Indianapolis area for the long-term are the ones who will eventually win out in the end. In the mean time, listen to Brett & Ronnie discuss some tips and tactics that could help you in your short game at this season of the real estate market.

This week, we talk about median playtime, weapon balance, and revisiting our older games. From chaotic co-op antics to echolocation-based platforming, our game jam experiments were always a blast, even if they were never quite commercially viable. But hey, you make some games for players and some just for the joy of making them.Support Crashlands 2!Official Website: https://www.bscotch.net/games/crashlands-2/Trailer: https://www.youtube.com/watch?v=ib7fzLf59voSteam Wishlist: https://store.steampowered.com/app/1401730/Crashlands2/Google Play:https://play.google.com/store/apps/details?id=com.bscotch.crashlands2Apple: https://apps.apple.com/us/app/crashlands-2/id152819933100:32 Intro00:50 Thanks to our supporters! (https://moneygrab.bscotch.net)01:04 Crashlands 2 Beta18:29 Marketing24:22 Balancing weapons33:28 Giantmuskrat: Would you replay your older titles on https://bscotch.itch.io/ and give them a score on the nailed it/whiffed it scale?To stay up to date with all of our buttery goodness subscribe to the podcast on Apple podcasts (apple.co/1LxNEnk) or wherever you get your audio goodness. If you want to get more involved in the Butterscotch community, hop into our DISCORD server at discord.gg/bscotch and say hello! Submit questions at https://www.bscotch.net/podcast, disclose all of your secrets to podcast@bscotch.net, and send letters, gifts, and tasty treats to https://bit.ly/bscotchmailbox. Finally, if you'd like to support the show and buy some coffee FOR Butterscotch, head over to https://moneygrab.bscotch.net. ★ Support this podcast ★

Brad Hutchings returns to discuss AI. Pete A Turner of the Break It Down Show has been working to use AI in some of his projects. He tried to find the Median debut for all baseball players. He did the work to find Detroit Tiger phenom, Jim Proctor who today is the middle player in all players, based on debut date, in MLB history (per baseball reference). Pete Writes about Jim in an article on X. Brad and Pete discuss Grok's inability to find the median player. Pete tried a few other AIs...they just don't work this way. Brad notes that AIs will give loquacious answers, but the results are more fantasy than fact. Then a funny test happens...what happens when you ask an AI, while offline, to reference an online resource...well...AI does a performance of giving an answer. This is a fun one.

Welcome to the "Saturday Morning Golf Stat" from the Hack it Out Golf Podcast. Today's episode brings us to new territory, as the TOUR's allows for more granular stats: how does green firmness affect how close a Tour pro can get to the pin? In this episode, Mark and Greg guess the median proximity for soft, medium, and hard greens. Lou brings the answer—and it will likely surprise you. How much difference do you think it makes? The guys then give a short discussion about how to make changes to your game to adjust to conditions so that you can shoot your best scores. Each of these will be a mini-episode (10-15 minutes long) about an interesting golf stat. We will discuss what you can learn, and most importantly, how you can apply this on the golf course to lower your scores and lower your handicap. Listen on your drive to the golf course or over your Saturday morning coffee! Data is sourced from Arccos Golf. They have over 1 BILLION shots in their database.  Check them out at: https://www.arccosgolf.com/  Use code MARK15 for 15% off! Learn more about your ad choices. Visit megaphone.fm/adchoices

Sheil Kapadia, Diante Lee, and Steven Ruiz kick off the show by reacting to Bill Belichick's proclamation that it's time to rename the Lombardi Trophy in Tom Brady's honor (00:00). Then, the guys discuss the floor, ceiling, and median outcomes for the Cowboys next season on the heels of the Brian Schottenheimer hire (03:02). Then, they do the same for the Raiders following their decision to bring in Pete Carroll (25:22). To round out the show, they take a look at potential offseason QB moves, how the Lions will fare without Ben Johnson (51:38), rumors of Kellen Moore to New Orleans (54:24), and some early thoughts on next weekend's Super Bowl matchup between the Chiefs and Eagles (59:58). The Ringer is committed to responsible gaming. Please visit www.rg-help.com to learn more about the resources and helplines available. Hosts: Sheil Kapadia, Diante Lee, and Steven Ruiz Producer: Troy Farkas Learn more about your ad choices. Visit podcastchoices.com/adchoices