POPULARITY
Noooo, byl to hustý týden! Začalo to už nedělním výletem do Znojma, odkud jde název a téma aktuálního dílu 111, a to je pasivně agresivní servis. Ale byly inspekční žně na Letné, v Olomouci, Brně. Do toho naše výročí s Veru, Klářiny osmnáctiny a naše společná Panelka a podcast, a do mikrofonu opět začmuchá i Karlík..). Venku je stále Zmrzlinová a Podcastová s U Kulatého stolu a Bomby k tyči. Tak slyšte a díky za vaši podporu na herohero.co/gastromapalukasehejlika - z té teď natáčíme 3 pořady (GastroSapa, brněnské anketky a Co je to za podnik s velvyslanci).
Večerná kázeň: Mt(6, 16-18) „Keď sa postíte, nebuďte zamračení ako pokrytci, ktorí si nasadzujú smutný výzor na tvár, aby ľudia videli, že sa postia. Veru hovorím vám: Majú svoju odmenu! Ale keď sa ty postíš, pomaž si hlavu a umy si tvár, aby nie ľudia videli, že sa postíš, ale tvoj Otec, ktorý je v skrytosti; Príspevok Čas pôstu – čas Božej milosti zobrazený najskôr Evanjelický a.v. cirkevný zbor v Žiline.
Send us a textCEO Mitch Steiner joins us on this week's collaboration with WTR Biotech Spotlight to talk about the next generation of drugs focusing on lean mass (muscle) preservation for obesity patients on the popular GLP-1 therapies. He reviews the recent enobosarm Phase 2b data and highlights the importance of functional clinical benefit in addition to maintaining lean mass. Listen to learn more about Veru and its obesity drug enobosarm.
Við komum við í Kling og bang úti á Granda og hittum þar listamanninn Sólbjörtu Veru Ómarsdóttir og ræðum við hana um sína fyrstu einkasýningu sem opnuð var þar í rýminu um síðustu helgi og nefnist Misskilningur í skipulagsmálum. En í verkunum skoðar hún hversdagslega hluti sem til eru innan veggja flestra heimila út frá tengslum okkar við þá en leitast einnig við að mæta hlutunum á þeirra eigin forsendum. Gauti Kristmannsson rýnir í Hjálparsagnir hjartans eftir Pjéter Ezterházy í þýðingu Jónu Dóru Óskarsdóttur, og Egill Arnarsson segir frá sínu uppáhaldstónverki.
Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma e Biotech world. Sage has rejected Biogen's unsolicited buyout offer and will seek strategic alternatives. Biogen and Eisai have received approval for a monthly maintenance regimen for Alzheimer's drug Leqembi. Veru's drug has shown promise in sparing lean mass in overweight adults on Wegovy. The Duchenne muscular dystrophy space is on the verge of a pivotal era with several companies developing investigational therapies. Akero has rebounded in a mid-stage trial, Daiichi Sankyo is optimistic for 2025, and Allakos is cutting its workforce. The text discusses the advancements in the Duchenne Muscular Dystrophy (DMD) space as it enters a pivotal era, with companies such as Capricor Therapeutics, Wave Life Sciences, and RegenxBio working on investigational therapies to address unmet needs. It also mentions Daiichi Sankyo's recent success with the approval of Astrazeneca-partnered Dato-DXD. Additionally, new treatments are in development for Achondroplasia to challenge Biomarin's Voxzogo. Novo's obesity drug shows promising results, Merck's Keytruda combo fails in a Phase III trial for GI cancer, and Tris Pharma wins late-stage for a non-opioid painkiller. The text also invites feedback from readers on topics they would like to see covered in the future.
Stāsta Latvijas Universitātes Literatūras, folkloras un mākslas institūta vadošais pētnieks Aigars Lielbārdis. Dzirksts, saukta arī par džirksti, džerksti, ir kādas locītavas, biežāk rokas izmežģījums, sastiepums vai saišu iekaisums, kas radies no pārpūles. Sāpošo locītavu grozot vai to viegli saspiežot, ir dzirdama džirkstēšana, gurkstēšana, klusa krakšķēšana – no šīs skaņas arī atvasināts kaites nosaukums. Dažkārt mūziķiem gadās pārpūlēt vai pārspēlēt roku. Latviešu tautas medicīnā jeb tradīcijās zināmi vairāki dziedēšanas paņēmieni – dzirkstes košana, dzirkstes nosiešana un dzirkstes ievēršana durvīs. Lai izpildītu minētās tautas ārstniecības procedūras, ir nepieciešami vismaz divi cilvēki, jo līdzās darbībai – spiešanai, ievēršanai vai nosiešanai – notiek dialogs starp abiem dalībniekiem. Pirmais prasa: „Ko tu tur dari?” Otrs atbild: „Dzirksti sienu” vai arī „Dzirksti veru”. Tad pirmais saka: „Sien, sien, kamēr nosien!” Vai arī: „Veri, veri, ka vari novērt!” Dzirksts spiešanu veic ģimenē pirmdzimtais bērns un pēdējais jeb pedelītis parasti vecā mēnesī. Tāpat arī siešanu veic noteiktā laikā – vecā mēnesī vai piektvakarā, darbība jāatkārto vairākas reizes. Ticējums no Lubānas vēsta, ka roka jāapsien ar sarkanu dzīparu. Tad slimais vaicā: „Ko tur sien?” Sējējs atbild: „Džerksti sienu!” Uz to slimais saka: „Sien, sien, kamēr izsien!” Saruna jāatkārto trīs reizes. Tad rītā roka esot vesela. Savukārt vēršana durvīs, kā liecina ticējums no Svētes, veicama piektvakarā un slimā roka jāver trijās durvīs. Pie pirmajām un otrajām durvīm vērējs saka: „Veru, veru!” Otrpus durvju viņam jautā: „Ko tu ver?” Pirmais saka: „Dzirksti veru!” Otrs saka: „Ver, ka vari novērt!” Pie trešajām durvīm saka to pašu, tikai vērējs beidzot piemetina: „Novēršu gan!” Tad dzirksts pārejot. Un labāk dzirksti ir vērt durvīs, pa kurām ir mironis nests. Iespējams, ka senākā pagātnē, bet varbūt arī ne tik senā, piemēram, vēl 19. gadsimtā šāds ārstniecības veids bija visai populārs latviešu vidū. Nenovēlu, bet ja nu tomēr dzirksts ir iemetusies kādā locītavā, šis būtu pirmais ārstniecības veids un pasākums, ko var veikt gan darbā, gan mājās. Turklāt, procedūra nav dārga! Un, kas zina – varbūt palīdz!
Europoslanci tento týždeň schválili nový kabinet Ursuly von der Leyenovej. Za hlasovalo 370, proti bolo až 282 europoslancov. Odborníčka na európsku politiku Barbara Zmušková v podcaste hovorí, že staronová šéfka komisie a jej kabinet získali najslabšiu dôveru poslancov v histórii. „Budú si musieť dávať väčší pozor, aby im prechádzali niektoré hlasovania. Von der Leyenová to bude mať náročnejšie a bude mať užší manévrovací priestor," hovorí.Proti hlasovali aj europoslanci za Smer, a tak v praxi nepodporili vlastného nominanta. „Bolo to viac politické gesto. Najmä keď videli, že sa nájde väčšina," myslí si Zmušková. V podcaste budete počuť aj reakciu europoslankyne Kataríny Róth Neveďalovej (Smer-SD). Spomedzi slovenských europoslancov hlasovali za kabinet Ursuly von der Leyenovej Miriam Lexmann (KDH), Branislav Ondruš (Hlas) a všetci poslanci Progresívneho Slovenska. V podcaste budete počuť Michala Wiezika.Podcast Európa vzniká v spolupráci s Európskym parlamentom.Moderuje Denisa Hopková.
Bývalý minister zahraničia z úradníckej vlády Miroslav Wlachovský opisuje, ako nám škodí zahraničná politika „na štyri strany“. V podcaste s Mirom Kernom vraví, že sme na tom v niektorých ohľadoch horšie ako Maďarsko za Viktora Orbána, ktorý bude mať na rozdiel od Roberta Fica za spojenca aspoň Donalda Trumpa.
#126 Silný výber – PRVÝ VÝROČNÝ DIEL! Veru, už je to rok, čo na Slovensku vládne štvrtý raz skupina pod vedením Robert Fica. Aj pri takejto smutnej príležitosti, možno priam práve pre ňu, sa patrí obzrieť, že čo a ako. A potom sa zhlboka nadýchnuť a ďalej sa pustiť do tlačenia tej povestnej káry plnej bolesti. Lebo po noci naozaj musí prísť deň. Raz. Niekedy. Silný výber. Prvá z posledných nádejí. Váš obľúbený podcast môžete teraz podporiť aj cez náš Patreon alebo kúpou šalomčeka: https://www.patreon.com/silnyvyber/membership https://www.buymeacoffee.com/silny_vyber Pripíjame a pripomíname: In memoriam Ľudka Borloková, narodeniny pána brata. Vivat amicenko Krajniak! Historický kalendár Janka Žideka (výber) 106 rokov od založenia I. ČSR (aj Martinskej deklarácie) Pred 203 rokmi sa narodil Ľudovít Štúr. 86 rokov od Viedenskej arbitráže Pripili sme si s: https://allesmuelleroderwas.de/produkte/kalinka-kefir-mild/pur Endorse: https://www.malamedvedice.cz/ Hudba v podcaste: George Gershwin – Rhapsody in Blue Odporúčaná hudba: Stano Petrov – Prečo to stále nejde https://www.youtube.com/watch?v=xP4Jzc3FH1A IMT Smile – Svet https://www.youtube.com/watch?v=LI3O8F94ndE
Forget Ozempic & Wegovy. The Biggest Opportunity In Weight Loss Today. Lose Weight, Not Muscle $VERU Guest: * CEO: Dr. Mitchell Steiner * Title: Founder, Chairman, CEO, and President * Website: www.verupharma.com * Ticker: NASDAQ: Veru * Bio: Mitchell S. Steiner, M.D., F.A.C.S. has served as President and Chief Executive Officer of Veru and as a director of the Company since October 2016. Dr. Steiner was the co-founder of Aspen Park and served as Aspen Park's Chief Executive Officer, President and Vice Chairman of the Board from July 2014 to October 2016. From 2014 to 2016, Dr. Steiner was a consultant and then the President, Urology and member of senior management of OPKO Health, Inc. (NYSE:OPK) and had responsibilities for the launch, marketing, sales and reimbursement of 4Kscore prostate cancer test to urologists and primary care physicians. Dr. Steiner was also the co-founder of GTx, Inc., a men's health and oncology public company, where he served as Chief Executive Officer and Vice Chairman of Board of Directors from 1997 to 2014. Dr. Steiner is a Board Certified Urologist and a Fellow of the American College of Surgeons and has held numerous academic appointments, including Assistant Professor of Urology, Cell Biology, and Pathology at Vanderbilt School of Medicine from 1993 to 1995 and Chairman and Professor of Urology, Director of Urologic Oncology and Research and the Chair of Excellence in Urologic Oncology at the University of Tennessee from 1995 to 2004. Dr. Steiner holds a B.A. in Molecular Biology and Chemistry from Vanderbilt University and an M.D. from the University of Tennessee. He performed his surgical and urologic training at The Johns Hopkins Hospital and postdoctoral research fellow in cell biology at Vanderbilt School of Medicine. --- Support this podcast: https://podcasters.spotify.com/pod/show/smartmoneycircle/support
Peti i poslednji sagovornik Danice Popović, profesorke Ekonomskog fakulteta u penziji, bio je vladika diseldorfski i cele Nemačke Grigorije. U sedamnaestoj epizodi Radar Foruma, sagovornici su razgovarali o zanimljivim religijskim, kulturnim i društvenim temama, i to s pozicija naizgled suprotstavljenih, a zapravo komplementarnih – profesorka Popović sebe određuje kao bogotražitelja, a vladiku je predstavila kao svešteno lice koje razume i crkvu i laike. „Čovek postavlja ateistička pitanja, ali čim ih postavlja, on traži boga. Pravi ateista bi bio samo neko koga ta tema uopšte ne interesuje. Kad u jevanđelju neki čovek moli Hrista da isceli njegovog sina ili slugu, nisam sada siguran, Hrist ga pita: 'Veruješ li', a on mu odgovori: 'Verujem, gospode, pomozi mom neverovanju.' Neverovatno paradokslano, a istovremeno jako istinito. Kad mi ljudi priđu kao svešteniku i kažu: 'Voleo bih da verujem, ali baš i ne verujem', kažem im: 'Ja isto tako', i onda malo zastanu. Jer, za veru se treba boriti. Za neverovanje se ne treba boriti, ono se uvek javlja samo“, predočava vladika. Na pitanje o položaju žene u crkvi, za koje se često može čuti da je podređen – recimo, žene mogu biti svetice, ali ne i sveštenice, vladika Grigorije je rekao da odgovora bezbroj, ali da nijedan neće biti dostatan. „Moj je utisak da je Hristos, glava i osnivač crkve, ženu podigao na mesto koje joj niko nikad pre njega nije dodelio. Žene su njegove učenice, putuju s njim, uče od njega i podučavaju druge. Na kraju su ostale s njim pod krstom, kad su se čak i apostoli razbežali“, kaže vladika. Više na www.radar.rs
Do štúdia relácie Pod tlakom prijal pozvanie zdravotnícky analytik Martin Smatana. Ten pred pár mesiacmi oznámil, že spolupracuje s ministerstvom obrany pod vedením Roberta Kaliňáka na výstavbe novej nemocnice v Prešove. V debate odpovedal na to, či má dôveru v Kaliňáka aj po viacerých jeho kauzách a ako garantuje transparentnosť pri výstavbe nového zdravotníckeho zariadenia. Preberali sme aj to, v akom stave je výstavba nových nemocníc po Slovensku, prečo podľa neho nie je dobré, že sa presunuli Rázsochy do Ružinova a zhodnotil aj ťažkú finančnú situáciu vo Všeobecnej zdravotnej poisťovni. Kauza trenčianskej kardiológie, kde je prítomný podľa medializovaných informácií len jeden lekár počas niekoľkých dní, je však podľa Smatanu nafúknutá. Čo si myslí o krokoch Zuzany Dolinkovej na poste ministerky zdravotníctva? Ako hodnotí to, že pandémiu na Slovensku prešetruje Peter Kotlár? Čo vôbec prinesie s tímom, kde sú viacerí popierači pandémie? Pozri si celý rozhovor o aktuálnych témach s Martinom Smatanom.
Ranná kázeň: J(10, 7) „I povedal im Ježiš znova: Veru, veru vám hovorím: Ja som dvere k ovciam.” Káže: Olinka Kaňuchová Príspevok JA SOM: Dvere zobrazený najskôr Evanjelický a.v. cirkevný zbor v Žiline.
Rieki, šķieti, velkumi, saivas, stelles un divvirziena izvilkums! Jau šo sestdien, 3. augustā, Vecpiebalgas „Vēveros” notiks pirmais Vislatvijas audēju saiets „Vēveru dienas Vēveros”. Kur radās ierosa jaunas tradīcijas iedibināšanai un par nedēļas nogalē Vecpiebalgā gaidāmo pasākumu stāsta četri lietpratēji - Latvijas Etnogrāfiskā brīvdabas muzeja projektu vadītāja Anda Skuja, Latvijas Nacionālā kultūras centra tautas lietišķās mākslas eksperte Linda Rubena, audējs, tautas daiļamata meistars, Tautas lietišķās mākslas studijas “Rīdze” vadītājs Māris Maniņš un Latvijas Amatniecības kameras tautastērpu meistare, TLMS "Rota" dalībniece Antra Šarlote Blome. Latvijas Etnogrāfiskā brīvdabas muzeja lauku ekspozīcijā Cēsu novada Vecpiebalgas “Vēveros” 3. augustā no plkst. 11.00 līdz 17.30 notiks pirmais Vislatvijas audēju saiets “Vēveru dienas Vēveros”. Svētkos aicināts piedalīties ikviens Latvijas audējs, lai kopīgi dibinātu jaunu tradīciju – audēju festivālu, kā arī ikviens interesents, kas vēlas saistoši pavadīt laiku, autentiskā vidē, izzinot senās amata prasmes un noslēpumus. 3. augustā “Vēveros” ar īpašām lekcijām uzstāsies Latvijas Etnogrāfiskā brīvdabas muzeja Etnogrāfijas departamenta vadītāja Dr.hist. Aija Jansone un krājuma tekstiliju kolekcijas glabātāja Aija Vistere, LU Vēstures institūta vadošā pētniece Dr.hist. Anete Karlsone, SIA “Mailīšu fabrika” vadītāja Ilze Mailīte, Carnikavas TLMS “Auseklītis” vadītāja Zane Ulmane. Būs daudzveidīgas radošās darbnīcas ap un par aušanu pieaugušajiem un arī bērniem, notiks aušanas darbnīcas “Vēverīšas” modes skate un Cēsu novada audēju kopu un studiju dižošanās. Varēs doties radošā pastaigā kopā ar Piebalgas rokdarbnieci Inesi Īris Liepiņu. Vecpiebalgas kolektīvu “Mudurainis”, “Slātaviņa” un “Mudurainis XO” dejotāji izrādīs skaistākās dejas, savukārt jauktā kora “Jaunpiebalga” dziedātāji aicinās sadziedāties, ar muzikāliem priekšnesumiem iepriecinās grupa “Dzilna” un Drabešu muižas muzikanti. Visas dienas garumā būs apskatāma “Vēverīšu” fotoizstāde, būs tirgus placis un iespēja ar muzeja gidiem doties bezmaksas ekskursijās pa “Vēveru” ekspozīciju.
„Veru, veru, hovorím vám: Kto počúva moje slovo a verí Tomu, ktorý ma poslal, má večný život a nejde na súd, ale prešiel zo smrti do života.“ Evanjelium podľa Jána 5:24 Pán Ježiš nás uisťuje o tom, kto má večný život a nebude súdený v deň súdu. Sú to všetci tí, ktorí počúvajú Ježišove slová, […] The post Zo smrti do života – 13. júl appeared first on evs.sk.
Veru, statočne ste nám naložili.... a preto sme sa museli patrične obhájiť :D Je pravda, že nie sme úplne jednoduché a zvládnuteľné, ale aby sme boli najhoršie znamenie, tak to si zas tiež nenecháme :D
Večerná kázeň: J(3, 1-12) „Bol farizej, menom Nikodém, popredný muž medzi Židmi. Ten prišiel k Nemu v noci a hovoril Mu: Majstre, vieme, že si učiteľ, ktorý prišiel od Boha; lebo nikto nemôže činiť znamenia, aké Ty činíš, ak len Boh nie je s ním. Ježiš mu odpovedal: Veru, veru, hovorím ti: Ak sa niekto nenarodí znova, Príspevok Vietor veje, kam chce zobrazený najskôr Evanjelický a.v. cirkevný zbor v Žiline.
Rusi už viac ako dva roky bez prestávky a krvavo útočia na Ukrajincov. Posledné správy z frontu neboli priaznivé. Ukrajincom chýbala munícia či pripravené obranné línie. Rusi naopak stále útočia všetkým, čo majú a rakety neustále lietajú aj do Kyjeva. Putin chce v armáde 100-tisíc nových brancov a jeho štát prepol na vojnovú ekonomiku.Na okraji Moskvy však zabíjali teroristi. Putin tomu zabrániť nedokázal, ani napriek varovaniam Spojených štátov či Turecka.Čaká teda Ukrajinu nová Ruská ofenzíva? Dokáže sa na ňu pripraviť a dokážu jej spojenci pomôcť? Čo sa deje v Rusku po zvolení Putina a teroristickom útoku? A čo robil Erik Kaliňák či Martina Šimkovičová v kremeľskom propagandistickom médiu? Braňo Závodský sa rozprával s analytikom Slovenskej spoločnosti pre zahraničnú politiku Alexandrom Dulebom.
Drs. Hope Rugo and Sara Tolaney discuss the promise of antibody-drug conjugates (ADCs) in the treatment of breast cancer, highlighting key trials that shed light on matching the right ADC to the right patient in the right setting. They also explore how combinations and sequencing of ADCs can augment their efficacy, the mechanisms of resistance, and the future potential of biomarkers to predict patient response. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco's Comprehensive Cancer Center. Antibody-drug conjugates, or ADCs, are rapidly changing the treatment landscape for patients with breast cancer. ADCs consist of antibodies that target tumor-specific antigens on the cell surface, chemical linkers, and cytotoxic payloads that can act powerfully to kill cancer cells. On today's episode, we'll be discussing advances in research to match the right ADC to the right patients and in the right setting. We'll also talk about the next steps, assessing how combinations and sequencing of ADCs can augment their efficacy, improve options for patients, and identify biomarkers in the future to predict how patients will respond so that we can match the right treatment to the right patient and their tumor. We need to gain a better understanding of the mechanisms of resistance that occur upfront as well as under the pressure of treatment. Joining me for this important discussion is Dr. Sara Tolaney. Dr. Tolaney is an associate professor of medicine at Harvard Medical School, associate director of the Susan Smith Center for Women's Cancer, and chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute in Boston. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Tolaney, we're delighted to have you on the podcast today. Thanks for being here. Dr. Sara Tolaney: Thank you so much for having me. I'm looking forward to the discussion. Dr. Hope Rugo: Great! So, we'll move forward, and because we're friends and colleagues, I'm going to refer to you as Sara, and I'm Hope, since we'll dispense with formalities in our discussion. A lot of the talks that we give about ADCs start out with “a revolution in breast cancer therapy.” And indeed, this is a really exciting time with ADCs as treatment for breast cancer, and we're rapidly moving these agents into earlier disease settings. Can you tell us a little bit about the possibilities and challenges of using ADCs for the treatment of breast cancer today? Dr. Sara Tolaney: It's interesting that you say antibody-drug conjugates as revolutionizing outcomes of breast cancer, which I think is true. But on the flip side, I think it's also bringing up a lot of questions about how to use them, when to use them, and how to manage side effects. So there are a lot of good strengths for these antibody-drug conjugates, but a lot of unknowns that we're still trying to figure out. We had an older antibody-drug conjugate T-DM1 that we were all very familiar with that for years had been a treatment that we used very commonly in metastatic disease and now even use in early breast cancer, and I think has changed outcomes for patients. But over time, we've been able to develop newer antibody-drug conjugates as the technology has really evolved so that these agents now are able to deliver a lot of chemotherapy into a cancer cell. We're seeing very high drug-to-antibody ratios, and we're also seeing that these drugs can function via bystander effect, whereas T-DM1, for example, was not able to do that. But our newer ADCs, like sacituzumab govitecan or trastuzumab deruxtecan, are agents that do allow chemotherapy to get into that cancer cell, but also to get into neighboring cells. And I think the technology evolution in being able to build these so-called next-generation ADCs has allowed for really unprecedented efficacy that we've not seen before. And it's also allowed us to develop these drugs in a way that's been different. Originally, we were developing T-DM1 to turn off HER2 signaling and to deliver chemotherapy into a HER2 cell. At least that's what we thought originally. And now we're really evolving so that we can just find a tiny bit of protein on a cancer cell and use it as a target, really in a subtype-agnostic way. And I think it's just a different way of thinking about how to use these agents to really deliver a lot of chemotherapy into cancer cells and have very robust efficacy. Dr. Hope Rugo: Yes, it is fascinating that some of the suppositions that we made with the first ADC don't seem to really hold true as well. And maybe they hold true in varying levels for the different ADCs. For example, this bystander effect is thought to allow us to target cells that have very low expression of the receptor that can be internalized even lower than our ability to detect these receptors by immunohistochemistry. And maybe we'll talk about that in a little bit. But first, you mentioned already sacituzumab and trastuzumab deruxtecan, the ADCs that are currently approved for breast cancer. But can you tell us a little more about those ADCs and the key trials that have led to approval of these targeted agents? Dr. Sara Tolaney: Yes, I think when we first saw the data that came out with T-DXd and DESTINY-Breast01, I think my jaw dropped because I had never seen a waterfall plot like that. This was a single-arm study that looked at T-DXd in patients with very heavily pretreated metastatic HER2-positive breast cancer and saw very high response rates of over 60% and a clinical benefit rate of almost 98%, meaning that almost every single patient who got the drug and had a median of six prior lines of therapy had reduction in tumor size. And that's unreal. I think it was revolutionary in the sense that we had never seen that kind of activity in such a pretreated population. The agent was studied in other registration trials, DESTINY-Breast03, which looked at T-DXd and compared it head to head with T-DM1 in a predominantly second-line metastatic HER2-positive population, and here, again, unprecedented results. I've never seen a p value like that or a hazard ratio of, again unreal, of a little under 0.3 and seeing a 28-month PFS with T-DXd relative to just a little under 7 months PFS with T-DM1. We have never seen patients with metastatic HER2-positive breast cancer have a PFS that long. Even in CLEOPATRA, it's a little under 19 months in the first-line setting, where people were predominantly naïve to HER2-directed therapies. This, again, is really changing outcomes for patients. But then, I think, when we go to the next step, we studied T-DXd in patients with HER2-positive breast cancer and it had again these unprecedented results. But there was some early data suggesting that it could even work in tumors that weren't truly HER2-positive but what we call HER2-low, meaning that they weren't HER2/3+, they weren't HER2-0 but they were 1+ to 2+ and not FISH amplified. And so even with a little bit of protein there, they were seeing activity in the early phase studies and so it led to DESTINY-Breast04, which compared T-DXd to chemotherapy of physician's choice in people who had had one or two prior lines of chemotherapy in the metastatic setting. It was predominantly geared to look at outcomes in hormone receptor-positive breast cancer. But there was a small group of 58 patients with triple-negative disease that were also included in that trial. And here again, a very unprecedented outcome seeing a response rate of about 50%, which, again, we never see in pretreated hormone receptor-positive disease. And a PFS of 10 months, and again, these are people who already had one or two prior lines of chemotherapy. So it's, again, really changing outcomes. And so now I think it leads us to a lot of other questions that we are addressing in trials - can this drug work even if the tumor has maybe no HER2 expression, what about HER2-0, what about HER2-ultra low, meaning a little bit of staining but not quite 1+. And so these are questions that I think we will need to address and there are studies that will help us address that. On the flip side, we saw sacituzumab govitecan get developed in breast cancer. Initially, we saw very impressive results from a single arm study of sacituzumab in metastatic triple-negative disease where we saw response rates of a little over 30%. These are patients who were very heavily pretreated with metastatic triple negative breast cancer where, unfortunately, response rates end up being in a 5% range so it was a home run in that setting. So that led to the ASCENT trial, which compared sacituzumab govitecan to treatment of physician's choice therapy and that study really enrolled people who were, in essence, second line and beyond in the metastatic triple-negative setting and showed almost triple progression free survival, in essence, doubled overall survival. So again, very robust efficacy leading to confirming its approval. And then we saw data from TROPiCS-02, which looked at sacituzumab in metastatic hormone receptor-positive disease and also showed improvements in both progression free and overall survival. And this was in pre-treated populations of 2 to 4 prior lines of chemotherapy. These agents, again, have established robust efficacy, and so now the idea is can we move these drugs earlier in development into earlier line settings and can we even move these agents into the early disease setting and potentially cure more patients? So hopefully, we'll figure out ways to make that happen. Dr. Hope Rugo: Yeah, that was a great summary of this exciting data. And I think we really got an idea of what waterfall plots could tell us from DESTINY-Breast01 where you could count the number of patients whose cancers grew with therapy on one hand. It's been a huge advance. I think it's where we get this “revolution” even in patients with a median of 4 lines of prior chemo, and, in the ASCENT trial, we were able to see this improvement and survival in the hardest-treated subset of metastatic breast cancer triple negative disease. And then the remarkable data in HER2-positive and HER2-low breast cancer hormone receptor positive disease. We're really covering all of the subset of breast cancers. When we introduce new therapies though, and of course, our interest is moving them earlier as lines of therapy in the metastatic setting, we really have to think about the adverse events and how those are going to affect their patients, and balancing the risk benefit ratio. Obviously when the benefit is so huge, we're more thinking about how do we proactively manage these side effects, educate our patients, use prophylaxis when possible. Can you share with us some of your insights on management strategies for toxicities? Dr. Sara Tolaney: You bring up a very good point, and I will say the ADCs were designed with the idea being that we could deliver a ton of chemotherapy into a cancer cell. So obviously, my hope had been that we weren't going to see a lot of chemotherapy-like side effects because the goal was to try to spare normal cells of these side effects. But unfortunately, we do see that these agents do have real toxicities, and I think that is an important message. So, for example, with sacituzumab, for people who have hair going into it, they will lose their hair during the course of treatment, and so that's important to make patients aware of. It can lower blood counts, and about 50% of patients who are on sacituzumab will end up needing growth factor support while they're on treatment. So, that is again something that needs to be monitored and managed. But usually, we're pretty good at managing neutropenia, and with the growth factor support, I find that it actually works really well. Another thing with sacituzumab is the potential risk of diarrhea, but most of the diarrhea is low-grade diarrhea. It's rare that you get someone who has high-grade diarrhea with sacituzumab. Usually, I find it works to just instruct patients to use loperamide as needed. And again, usually that works well. And certainly when needed, dose modification can also help with these side effects and so it is important to keep in mind that this is another option. With T-DXd, one thing that we do have to keep in mind as an unusual side effect is the potential risk of interstitial lung disease. We see that in about 10% to 15% of patients getting T-DXd. That is something that we do have to be very mindful of. For the most part it is low-grade ILD. But there are rare occasions where there have been deaths from ILD. And we're seeing with some of the newer trials, the death rate is usually under 1%, but it is a real potential risk. And so it is really important to counsel patients when getting T-DXd about this potential side effect, that way they are good about communicating with you if they get any new symptoms, such as shortness of breath or dry cough, to get you aware of it and can work it up and get imaging certainly if that occurs. And then I think the management for ILD is a little unique and a little different truthfully than the way we manage pneumonitis from other drugs. Normally, when I am treating patients who develop pneumonitis, even if it is mildly symptomatic, we often will hold treatment, give steroids, and rechallenge them when it gets better. But with T-DXd, if anyone develops symptomatic pneumonitis, you actually have to permanently discontinue the T-DXd per the guidelines because we just don't know the safety of being able to rechallenge that patient once that pneumonitis resolves. For grade 1 ILD, meaning someone who has, for example, ground glass changes seen on imaging but doesn't have any symptoms, you have to hold the drug and wait until those imaging findings resolve and then you can restart. I usually do treat grade 1 ILD patients with steroids with the hope being that maybe it will allow for the pneumonitis to resolve more quickly, although in truth I don't know if that's the case. I have just taken that approach because I don't like leaving patients off the drug for too long if not needed. Again, I typically treat them with steroids, reimage in three to four weeks, and see if I'm able to restart. If they resolve within 28 days, you can restart at the same dose. If it takes longer to resolve, you need to dose modify. And then I think the other big thing with T-DXd is to know that it is categorized as a highly emetogenic agent. Most of us are using three-drug prophylaxis, which I think works really well. It is also important to realize that there can be some delayed nausea, which is a little unusual with some of our other agents. And so to warn patients about that and I find that use of olanzapine or ondansetron for the delayed nausea tends to work pretty well. Hope, do you have any pearls for us? Obviously, you are very experienced in using these agents; are there any things you would recommend for the management of ADCs? Dr. Hope Rugo: Yes, it's such a great question and an important area because, particularly as we are using these agents earlier, we really need to have strategies for both how long to continue as well as manage the toxicities. I agree with the nausea, olanzapine has been really a great addition, and using a triplet as initial premedication makes a big difference for T-DXd and other deruxtecan ADCs that are in the pipeline. And then I think that the ILD issue, we're really learning more about the risk factors as well as retreatment. And hopefully, we'll have more data this year at ESMO Breast and maybe ASCO on retreatment for grade 1. We certainly now do not have any data on the safety of retreatment for grade 2, so that is really not accepted now. For sacituzumab, I think the interesting area is the metabolism and the impact. So with neutropenia, as we move the drug earlier, it's easier and easier to manage, we see less severe neutropenia. We can give growth factors, which we are all good at in oncology. But I think the question about managing diarrhea and who is at risk still exists. Understanding pharmacogenomics and UGT1A1 is an interesting area where patients who have diarrhea could be tested to see if they are poor metabolizers which affects a little under 10% of the overall population. Because in that group, you could give less drug and get the same benefit with less toxicity. So I think this is all very interesting. It is important for providers and patients to be educated so that we can manage this appropriately. And I think you gave an excellent overview. We have new agents in the pipeline also and maybe we'll talk about those next, and then we'll talk a little bit about sequencing and resistance, as well as the unmet need for brain metastases. So lots of areas to talk about. There are a number of TROP-2 ADCs that are in the pipeline, and one that has presented phase III data, datopotamab deruxtecan. But other studies are being developed with new TROP-2 ADCs as well. But then there are a huge number of ADCs there with new targets, for example, immune effector targets, and new payloads, even immunotherapy and two different payloads or bispecific antibodies. And then there is interest in combining ADCs with immunotherapy and PARP inhibitors. We saw data in bladder cancer, I think it was bladder cancer, with combined 2 different ADCs at ESMO in 2023. So a lot of new approaches. How are we going to manage this moving forward? And where do you think we are going to position some of these next sort of "me-too" drugs? Dr. Sara Tolaney: It's an excellent question, and you're right, the field is exploding with new antibody- drug conjugates. So, it's going to leave us with this conundrum of what to do. And you brought up the really interesting example of the fact that we have an approved TROP-2 ADC, we have as sacituzumab govitecan, and for example, we've recently seen some really exciting data come out from TROPION-Breast01 looking at another TROP-2 ADC, datopotamab deruxtecan or Dato-DXd where that ADC performed better than chemotherapy in a head-to-head trial in terms of progression-free survival in a hormone receptor-positive population. Then there's another TROP-2 ADC, moving forward in development moving to phase III that Merck is developing MK-2870. All three of these ADCs are targeting TROP-2 and have a TOPO 1 payload. So, it leaves you with the question of how do you think about that? Is there going to be a role for using serial TROP-2 ADCs? Could one work after the other, even when they have very similar payloads? How are we going to incorporate them? How do you pick one over the other? So, it is going to be tricky for us as we get more and more of these agents. I think we're all excited about seeing ADCs that may have different targets and different payloads, where maybe we will see that sequential utilization will have robust efficacy if we swap things out. Again, we don't have data here yet, but I think there are other agents in development. For example, you could think of like, disitamab vedotin targets HER2 and has an MMAE payload. So, could it be that someone progresses on T-DXd for HER2-low, but then could go on to disitamab vedotin? How will that work? So, we have a lot to learn, but it's really nice to have so many options. Dr. Hope Rugo: Yeah, it'll be interesting to see whether or not we select the ADC based on a rational understanding of the tumor and the patient, or whether it's simply what's easier to give and has the right toxicity for that patient. So, that sort of brings us to our next topic, which is how are we going to sequence these agents? How are we going to understand the mechanisms of ADC resistance? At San Antonio in 2023, we saw a presentation where there was a top-alteration, and the patient had a really long response to a top-directed ADC, or an agent that carried a topoisomerase inhibitor. And that really struck me that we're going to see these alterations. There was a fresh autopsy study that suggested that the alterations may be different in different organ sites of disease. How are we going to figure this out? Dr. Sara Tolaney: Yeah, I also was really puzzled to see those data from San Antonio where we've sort of simplified ADC resistance in our heads to say, well, maybe someone becomes resistant because they lose target expression, or maybe someone becomes resistant because they've developed resistance to the payload, kind of like the way we think of someone developing resistance to getting chemotherapy. But obviously, it's probably far more complex than that. With these ADCs, they need to be able to internalize the ADC and could there be mechanisms of resistance related to the internalization process? So, I think there are lots of potential areas where resistance could be occurring. I think, we don't understand it very well. We've seen patients, for example, who have responded. This is just anecdotal, but we have data, for example looking at, Dato-DXd in the phase 1 triple-negative study where there were some patients who responded despite having progressed on sacituzumab. Well, why is that? You would think if it's target resistance or payload resistance, it would be the same target and a very similar payload. So, why would those drugs work one after the other? And that's why I think we just don't understand this well enough at this point in time. So, it's clearly an area where more research is needed because it does have significant implications on how we think about using these drugs sequentially. We will need to understand these resistance mechanisms because there do seem to be some rare patients who benefit from these sequencing strategies and then others who don't. So, it would be nice to be able to figure this out and hopefully in the future, we'll be able to test patients and know what drugs to give them. But I think we're far off from that, unfortunately, right now. Dr. Hope Rugo: Yeah, it does seem to be a relatively elusive approach, and I think, in part, it's due to the heterogeneity of cancer. And maybe, as we're better and better at analyzing tumor cells in the blood, which are a rare group, and ctDNA, which, of course, we do now to look for mutations, maybe that'll be an approach that we'll be able to take. And also, of course, moving the drugs earlier into the disease setting with less heterogeneity and mechanisms of resistance might help as well. I was fascinated by the fact that although the PFS to the first ADC seems to be overall much greater than the PFS to the second ADC, when you sequence them, there are a few patients who have a longer PFS with the second, even if these are just sacituzumab T-DXd sequencing in various directions. So, it's clearly very complex. And right now, I think we're just sequencing and we don't really know how to do it. We just choose what we think is best for that patient first and go on to the next one later, which is interesting. And one of the choices might be treating brain metastases, which of course remains a huge unmet need. And if we could find effective treatment for brain metastases, maybe we could also prevent them in some patients more. What do we know about the central nervous system (CNS) penetration of ADCs and the clinical results? Dr. Sara Tolaney: At first, we were not optimistic that these drugs would have activity in the brain because we thought that these were very large agents that probably couldn't penetrate into the blood-brain barrier. But in fact, I think we were all very excited to see that there is actually data suggesting that these drugs can actually have robust efficacy in the CNS in patients who have active brain metastases. And so what we've seen so far is data with trastuzumab deruxtecan or T-DXd, there have been some trials that have been done, including studies like DEBRA and TUXEDO, which have looked at T-DXd in patients who have active brain metastases and are showing very robust response rates within the CNS. So, we're seeing intracranial response rates on the order of 40% to 50%. And clinically, this is what we're seeing as well. These are smaller studies and there's a larger trial, DESTINY-Breast12, which will hopefully validate the robust efficacy in the CNS with T-DXd. So, again, it's really nice to see this. To your point, though, one area that I'm curious about, as you were alluding to, is will these drugs be able to prevent CNS disease? And I think that is a very different question because here the blood-brain barrier is not intact when patients have progressive brain metastases, and so these ADCs are causing robust activity. But if you look, for example, and I'll be curious to see what happens, DESTINY-Breast05 is looking at T-DXd in the post preoperative setting for patients who have residual disease and comparing it to T-DM1. And unfortunately, we saw that T-DM1 was not able to prevent brain metastases when looking at data from KATHERINE, where in fact, rates of CNS as the first site of recurrence were similar with T-DM1 and trastuzumab. So, now we'll be interested to see, will it be any different with T-DXd? Will T-DXd be able to have any role in prevention? I think we haven't seen anything like that with ADCs to date, so that would be a paradigm shift in our way of thinking. Right now, there are strategies being taken from a prevention standpoint of trying to add a tyrosine kinase inhibitor in that early-stage setting, such as what is being done in the COMPASS-RD trying to add tucatinib to T-DM1 to see if that would do it. But again, we really need to understand, again, how these drugs work, particularly when the blood-brain barrier may not be intact. But again, very exciting data with T-DXd in an ongoing trial, actually through SWOG looking at sacituzumab for patients with CNS disease. And we've seen some preliminary data with sacituzumab showing that it actually does penetrate into the brain when they've looked at drug levels in the tumor in the brain, comparing it to plasma, it actually looks similar. So, we know it's getting in there and we'll have more robust efficacy data, hopefully coming soon. Dr. Hope Rugo: Yeah, that was a great summary of that data. It's been exciting also to see some responses in patients with leptomeningeal disease as well, where we've really been struggling with anything that works for more than a few weeks or months at the most. So I'm holding out great hope that we're going to see a big difference because even though TDM-1 had some efficacy, it was nothing like what we're seeing with T-DXd. So we'll see. And the same with sacituzumab with triple negative disease, where sometimes brain metastases can be an isolated site of recurrence, even in patients who have a pathologic complete response. So it has been a big challenge. So I think that what we've learned from you is a lot about the mechanisms and the data about these new ADCs, the tremendous hope that these are bringing to our patients, but also the really exciting new approaches with new payloads, new targets of drugs that are in development, as well as potentially some different ADCs that have the same target and similar mechanisms of action of this payload. Really fascinating to hear about this, the future work on sequencing, on mechanisms of resistance, and on brain metastases. We have, of course, 2 prospective trials that we'll be looking at sequencing, one with T-DXd and Dato-DXd, and one registry trial with T-DXd and sacituzumab govitecan in the US. So that's also going to, I think, provide us with some important information. We could talk for a long time about this, but I just wonder if you have any closing comments to sum up your thoughts. Dr. Sara Tolaney: I think you did a great job leading us through thinking about ADCs, and I think it'll be really interesting to see what happens in the future. While again, these agents have become a standard for us for patients with metastatic disease, I'm going to be curious to see how everything evolves and to see if we'll be able to substitute chemotherapy with ADCs in early disease settings and change outcomes. Will we be able to have novel combinations? Will we be able to sequence these drugs one after another? Will we actually have biomarker predictors to help us sort out which drug to give when? So, still a lot to learn, but clearly a very exciting field right now. Dr. Hope Rugo: Indeed. Sara, thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast on your great work to develop novel therapies for breast cancer. It's always a pleasure to talk to you, and even greater to work with you on the future progress of treatment for breast cancer. Dr. Sara Tolaney: Thank you so much, Hope. Again, really nice to always discuss these data with you. I always learn a lot, so thank you. Dr. Hope Rugo: Thank you. And thank you to our listeners for joining us today. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of a product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Hope Rugo @hoperugo Dr. Sara Tolaney @stolaney1 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Hope Rugo: Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc, Stemline Therapeutics Travel, Accommodations, Expenses: Merck, AstraZeneca Dr. Sara Tolaney: Consulting or Advisory Role: Novartis, Pfizer, Merck, AstraZeneca, Genentech, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Immunomedics/Gilead, BeyondSpring Pharmaceuticals, OncXerna Therapeutics, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Umoja Biopharma, Menarini/Stemline, Aadi Bio, Artio Biopharmaceuticals, Incyte Corp, Zetagen, Bayer, Infinity Therapeutics, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR Therapeutics, Hengrui Pharmaceutical (USA), Sumitovant Biopharma Research Funding (Inst.): Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Seattle Genetics, OncoPep, Gilead Travel, Accommodations, Expenses: Eli Lilly, Sanofi, Gilead Sciences
15.umferðin í Olís-deildinni var gerð upp í þætti kvöldsins. Slúðurmolarnir voru fjölmargir og áhyggjuefnin ekki færri. Hvaða fimm félög heyrðu í Halldóri Jóhanni? Hvert fer Einar Baldvin? Rasimas hefur fengið kveðjubréfið á Selfossi og AP4 hefur fengið hvíld fyrir bikarleikinn gegn Haukum. Sjö umferðir eftir og staðan í fallbaráttunni er stórhættuleg.
Vyplňte podcastový prieskum a pomôžte nám zlepšiť váš poslucháčsky zážitok - sme.sk/prieskum Takmer 90-stranový dokument s názvom Lepšie, pokojnejšie a bezpečnejšie žiť odobril parlament. Kým koalícia programové vyhlásenie považuje za obraz silného a sociálne spravodlivého štátu, opozícii v ňom chýbajú opatrenia, ktoré skutočne dokážu zlepšiť stav verejných financií. Nakoľko vôbec plánuje súčasný vládny kabinet šetriť, kde chce získať peniaze na ďalšie sociálne opatrenia a treba sa pripraviť na vyššie dane alebo pôjde cestou výdavkov? Eva Frantová sa v podcaste Dobré ráno pýta ekonomického redaktora magazínu Index a denníka SME Jozefa Ryníka. Odporúčanie: Budúci rok nečakajú prezidentské voľby len Slovensko, ale aj Spojené štáty americké. Skutočnosť, že by Joea Bidena vystriedal exprezident Donald Trump pritom nevylučujú viaceré prieskumy. Ak sa chcete dozvedieť viac o tom, akým obvineniam v súčasnosti čelí, odporúčam utorkové (21. 11.) vydanie denného podcastu Today in Focus od spravodajského portálu Guardian, kde sa Trumpovmu vyčíňaniu venujú do detailov. – Všetky podcasty denníka SME nájdete na sme.sk/podcasty – Odoberajte aj audio verziu denného newslettra SME.sk s najdôležitejšími správami na sme.sk/brifing – Odoberajte mesačný podcastový newsletter nielen o novinkách SME na sme.sk/podcastovenovinky – Ďakujeme, že počúvate podcast Dobré ráno.
Premiér Robert Fico dnes predložil v Národnej rade programové vyhlásenie vlády a zároveň nová vláda žiada aj o dôveru v parlamente. Opozícia programové vyhlásenie kritizuje a podľa nej je vágne, plné vaty a nekonkrétne. „Nechcem o vláde, ktorá sedí za mnou hovoriť, že je najlepšia na svete, že je najreformnejšia. Chcem o nej hovoriť ako o vláde Slovenskej republiky, ktorá sa vyskytla v konkrétnom čase a vznikla z výsledku parlamentných volieb a stojí pred viacerými výzvami,“ reagoval Robert Fico v úvode svojho dnešného vystúpenia pred poslancami Národnej rady. Igor Matovič počas dnešného dňa v parlamente kritizoval vládu näjme z dôvodu, že podľa neho oklamali svojich voličov a neplnia sľúbi, ktoré im pred voľbami dali. Michal Šimečka z Progresívneho Slovenska označil plán vlády ako vágny, nekonkrétny a deravý. Očakáva, že rovnaké bude aj vládnutie Ficovej vlády.Opoziční poslanci sa dnes pokúsili odvolať podpredsedu parlamentu Ľuboša Blahu. Návrh na jeho odvolanie v parlamente ale neprešiel. Opozícia mala len 69 hlasov, pričom potrebných bolo minimálne 76 poslancov. Lídrovi KDH Milanovi Majerskému sa nepáčia kroky novej koalície, ktorá sa hlási k EÚ, no zároveň podpredseda parlamentu schováva jej vlajku do skrine. Majerský bol kritický aj k programovému vyhláseniu vlády, ktoré je podľa jeho slov nekonrétne. Vidí tam ale aj pozitíva, medzi ktoré patrí zmena volebného systému. KDH by takúto zmenu podporilo.
Premiér Robert Fico dnes predložil v Národnej rade programové vyhlásenie vlády a zároveň nová vláda žiada aj o dôveru v parlamente. Opozícia programové vyhlásenie kritizuje a podľa nej je vágne, plné vaty a nekonkrétne. „Nechcem o vláde, ktorá sedí za mnou hovoriť, že je najlepšia na svete, že je najreformnejšia. Chcem o nej hovoriť ako o vláde Slovenskej republiky, ktorá sa vyskytla v konkrétnom čase a vznikla z výsledku parlamentných volieb a stojí pred viacerými výzvami,“ reagoval Robert Fico v úvode svojho dnešného vystúpenia pred poslancami Národnej rady. Igor Matovič počas dnešného dňa v parlamente kritizoval vládu näjme z dôvodu, že podľa neho oklamali svojich voličov a neplnia sľúbi, ktoré im pred voľbami dali. Michal Šimečka z Progresívneho Slovenska označil plán vlády ako vágny, nekonkrétny a deravý. Očakáva, že rovnaké bude aj vládnutie Ficovej vlády.Opoziční poslanci sa dnes pokúsili odvolať podpredsedu parlamentu Ľuboša Blahu. Návrh na jeho odvolanie v parlamente ale neprešiel. Opozícia mala len 69 hlasov, pričom potrebných bolo minimálne 76 poslancov. Lídrovi KDH Milanovi Majerskému sa nepáčia kroky novej koalície, ktorá sa hlási k EÚ, no zároveň podpredseda parlamentu schováva jej vlajku do skrine. Majerský bol kritický aj k programovému vyhláseniu vlády, ktoré je podľa jeho slov nekonrétne. Vidí tam ale aj pozitíva, medzi ktoré patrí zmena volebného systému. KDH by takúto zmenu podporilo.
Po vraždách Jána Kuciaka a Martiny Kušnírovej v roku 2018 sa téma korupcie dostala do stredobodu pozornosti v rámci verejnej diskusie. Hovorilo sa veľa o korupčných kauzách, o vyšetrovaní uneseného štátu a o právnom štáte ako takom. Na tento vývoj zareagovala aj tzv. alternatívna mediálna scéna, pre ktorú dovtedy tieto kauzy neboli ťažiskové.Ako vnímajú ľudia témy korupcie a právneho štátu v porovnaní s reálnymi dátami? Koľko percent oslovených ľudí sa v prieskume Transparency International priklonilo k alternatívnym názorom o témach ako je špeciálna prokuratúra, samovražda Milana Lučanského alebo údajná manipulácia volieb? Ako často informovali o témach z oblasti právneho štátu a boja proti korupcii alternatívne médiá? Nakoľko sa frekvencia informovania líšila v porovnaní s mainstreamom? Existovali aj témy, ktorým sa alternatíva venovala viac ako štandardné médiá? Aké zdroje využívali alternatívne médiá pri informovaní o jednotlivých témach? Nakoľko sa objavovalo zdieľanie obsahu z tlačových agentúrach či publikovanie názorov influencerov a politických predstaviteľov? Ktorí politici boli citovaní najviac? Dokázala sa alternatívna scéna voči niektorým konšpiračným teóriám aj vyhraniť? Ktoré politické strany si pred voľbami platili propagáciu v alternatívnych médiách a prečo je takáto reklama problémová? Aké nedostatky a pochybenia v rámci novinárskych a etických štandardov boli typické v článkoch alternatívnych médií?Aj o tom v novej epizóde podcastu Disinfo Report organizácie Infosecurity.sk hovorí Tonka Zsigmondová s riaditeľom Transparency International Slovensko Michalom Piškom.
Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo: You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a third to a half of breast cancers after exposure to aromatase inhibitors, that's led to really an explosion, this alphabet soup of possibilities that you talked about. SERMs, selective estrogen receptor modulators, tamoxifen is the classic one—something that acts as an agonist and as an antagonist, depending on the tissue. The SERDs, the selective estrogen receptor degraders, lead to estrogen receptor destruction. Fulvestrant is the classic example of this right now. But we're very excited that a second one has been FDA approved. That's elacestrant that was approved earlier this year, and it has specifically been developed to try to target those estrogen receptor mutant breast cancers because those are the ones that are particularly resistant. So that's the first of this new generation of SERDs that's coming on the market, has come on the market. As you say, a key advantage there is that it's oral, unlike fulvestrant, which requires 2 monthly injections and is very, very inconvenient and uncomfortable for patients. Other SERDs are coming along. I think another one that is well along in clinical development is giredestrant, which is in the same family and being tested in clinical trials of the classic varieties. It's been tested in a window trial, looking at its ability to down-regulate Ki67. It's being tested against standard of care in first-line metastatic breast cancer. And there are some studies that are going to begin looking at it in the adjuvant setting as well. There are other members of this particular family, but I think that elacestrant is the one that we have at our fingertips right now, and giredestrant is one that's certainly coming along in clinical trials, and we should look forward to those results. For those who are interested in the giredestrant, the trials in question right now that are going on are persevERA, which is in stage 4 breast cancer, and lidERA, which is in the adjuvant setting. Now that's one new category, or it's an old category with a new twist. A second is these agents that are called complete estrogen receptor antagonists, CERANs, as you talked about them. The key here is that what they do is, the estrogen receptor has a couple of domains, and in particular, it has 2 different activation domains, AFT1 and AFT2. And these CERANs are complete estrogen receptor antagonists, so they block both of those domains. And the hope would be that they might end up being more effective than the other agents that we have available to us right now. So those are also in clinical trial at the present time, and we're waiting to see whether or not there's going be any value in that particular area that's going to able to go forward for us. Another area that I think we want to talk about is the PROTACs, as you mentioned. These are proteolysis targeting chimeric entities. So, this is a kind of a complicated situation where you have a kind of bivalent situation where you have something that binds both to the estrogen receptor and then also to E3 ubiquinase. So, it leads to degradation again of the agents; that's another area for us to be watching. And then finally the SERCAs. So those are the selective estrogen receptor covalent antagonists, and what they do is they bind very specifically to a cysteine 530 that exists in the estrogen receptor but not in other steroid receptors. So that's where the selective part of this comes along. Now these are all in various stages of clinical investigation. Some of them are pretty early at this point, but I think the ones that are well established are elacestrant, giredestrant is coming along as we just talked about. Camizestrant is also coming along through the SERENA series of trials, and imlunestrant is also coming on through the EMBER series of trials. Hope, I would also be remiss if I didn't go back to an old drug that's a new drug, and that's lasofoxifene, which is also in the SERM family. Those who have been in our field for a while will remember that lasofoxifene was actually originally kind of tested in the prevention setting, where it seemed to have some activity. It came back into our interest because it has really strong activity against estrogen receptor mutant breast cancer models in the laboratory. And as a consequence of that, it's coming back into the clinic through a series of trials that are called the ELAINE trials, where we're looking to see whether or not it might also be better than fulvestrant. It too is an oral agent, so that's a real plus for us, and the first set of ELAINE trials would suggest that there's some nice activity without a lot of toxicity. So, lots going on in this field. You know, I think for all of these things, obviously, we're also working very hard to think about the toxicities. All of these, as I recall, are oral agents. So that gets rid of 1 huge toxicity, which is you don't have the need for some sort of injection. But they all do have some side effects. Frequently, [the toxicities] are like GI side effects or fatigue. In a couple of cases, there might be some concern about cardiac arrhythmias, but I think GI turns out to be one of the most important things that we have seen in some of these trials. Generally, it's very well tolerated, though. I think another important question, which I'm sure is in your head and is in mine, is that how are we going to integrate these into what we already have? And so, I think a lot of the work right now is looking at patients who have already received an aromatase inhibitor plus a CDK4/6 inhibitor and are now going on to one of these new agents. But you might wonder, if they turn out to be effective and well-tolerated, whether they too should be perhaps combined with CDK4/6 inhibitors in place of the aromatase inhibitors or the fulvestrant that we use now. So, I think that we can imagine that those clinical trials are either in progress in some cases or will be coming on as we try to think about how to integrate these new approaches into our existing standard of care, which is already quite complicated, right? We've gone far from tamoxifen, which was good for everybody, to now a really complex algorithm about how we think about hormone therapy, both in early breast cancer and in metastatic breast cancer. Dr. Hope Rugo: Well, that was a fabulous discussion about the new agents and our existing agents and both the exciting aspects, as well as the challenges. One question that comes up, I think a lot, and this is of course a huge question in many ways, but for ER-positive metastatic breast cancer, where these drugs are first being tested, maybe we'll talk about that first. There's one trial at SERENA-6, looking at camizestrant in patients who have developed evidence of an ESR1 mutation in circulating tumor DNA, who are on first-line therapy with an AI and a CDK4/6 inhibitor. What do you think about that study and where do you think that progress might go? Of course, that's based on data from another trial, which wasn't definitive, but suggested, had sort of a suggestion, you know, without studying the sequencing in detail that maybe you would have improved progression-free survival with that approach. Dr. Nancy Davidson: Yeah, by which you mean the idea of monitoring pre-ESR1 mutations and circulating DNA and then making therapy changes based on that? Is that what you're talking about? Dr. Hope Rugo: The PADA-1 trial, yes, and that led to this huge SERENA-6 trial, which of course is now accruing. Dr. Nancy Davidson: So, you know, we would love that, right? I think that obviously breast cancer for many years has been interested in trying to have circulating markers that we could use to help to guide our therapy in a more meaningful way than we have in the past. And I think that the trial that you've talked about is certainly one that's trying to make that see whether that's a possibility for us based on information like the PADA trial. I'm hopeful it's going to work out. I would say, let's see what that looks like, whether it's going to be useful or not. It seems to me in some cases, some of these trials have not been quite what we hoped for, but I don't think we necessarily had the molecular techniques or the sensitivity, nor did we necessarily have other things to move to because, you know, those two approaches require both a really good test, but also the ability to use the test to define a new therapy that's going to lead to improved patient outcomes. And I think that these are ingredients that we now have available to us at our fingertips more than we did, say, a decade or 2 decades ago. Exciting approach. Dr. Hope Rugo: I do think there's a lot of challenges inherent in this process, monitoring blood on a regular basis and following up and then randomizing based on results. But I think [SERENA-6] is an incredibly important trial, as you have mentioned, to try and think about moving past using circulating tumor cells, which didn't work, to just change blindly to the next therapy, but more have a rational reason to change to a drug that may be more effective before the disease itself progresses. And just for our listeners, the unique aspect of trials like this in SERENA-6 is that you change therapy before you have evidence of disease progression, but only this molecular evidence of a mutation that is associated with resistance to the therapy you're on. So, it's a really important question. We'll see what happens, as you mentioned, sometimes we're not clever enough to really get around the fact that there are multiple mutations driving resistance in this setting, so we'll see how straightforward this is. The question also comes up, and I think that's a question with many of these trials now, is they're randomizing patients after a progression on an AI and CDK4/6 inhibitor to receive the novel endocrine therapy or fulvestrant. One of, I think, the concerns of treating oncologists is that then you're sort of eliminating the possibility of a targeted agent in that setting. And of course, we have new targeted agents we're studying as well, AKT inhibitors and new inhibitors of the PI3 kinase pathway. So, the newer trials are now combining, as you mentioned. There's a lot of concerns about drug-drug interactions here and how you might really combine them. And then there are triplet studies looking at CDK4/6 inhibitors, oral SERDs primarily, and pi3-kinase and CDK4/6 inhibitors. What's your thought on these and will they really help to move the needle forward? Dr. Nancy Davidson: I think that's a really interesting question, Hope, is whether or not we're going to find that combination therapies from the get-go are the way to go, or whether we're going to end up having to use maybe more serial therapies. Because not only is it a question about whether or not you can tackle all of these different resistance mechanisms simultaneously, but I think the other question is, as you say, are there negative drug-drug interactions, and are there toxicities that are intolerable? Although these are targeted in all cases and they're relatively benign in terms of side effects from the breast cancer perspective, they're not devoid of toxicity. And so, I think that's going to be another issue for us – whether they're well tolerated during the time that patients are taking them. I guess the other thing I always think about, Hope, is that it's hard to know about value of cancer care, but you know, we are talking about agents that are not inexpensive. You know, when you think about the financial toxicity, in addition to the side effect toxicity that you and I just talked about, trying to think about what that value is going to look like is going to be very important for us. Also, as somebody who worked for a long time in the lab and in the clinic, you know, there are an infinite number of combinations that you and I could think about that are rational. And so, the question is, how are we going to pick the ones that are the most rational, if you will, the ones that seem to be the most promising, and take them forward into clinical trials? Because patients are our most precious resource. And so, we want to make sure that we are bringing forward only those things that really seem to have a very strong foundation and the opportunity to improve outcomes over time. Tough, tough question for us to try to think about, as you've talked about. The other thing is that, you know, these trials are not only for postmenopausal women, who are the majority of patients, but we also want to target them to premenopausal women. So, in those women, we're also looking at using an LHRH agonist on top of this, right, because many of these things are really at least so far designed for the postmenopausal state. So stay tuned. Lots of work going on. I think one of the interesting things will be making the leap from using these in metastatic disease at time of progression to taking them forward into the early breast cancer space. And several of the agents are now beginning to do that because of very strong preclinical and clinical data to date. Dr. Hope Rugo: So, we have new agents that we're studying in the metastatic setting, and we've seen a trend to move fairly rapidly from phase 1B trials directly into phase 3 trials, because as you pointed out so clearly, there are a number of drugs in this setting, and we don't really know not only which agent is better, but even what class of agents is better. So, as we move more quickly from phase 1B to phase 3, the question comes up about how we're going to study these agents optimally in the early-stage setting. They, I think we all thought that maybe changing based on ctDNA evidence of a mutation might be an approach, but that's complicated. A big question for you is whether or not you think that's ready for prime time as it's being marketed as such. And then the second question is really, are we better changing our whole approach upfront in high-risk disease or should we wait until after patients are exposed to their endocrine therapy and then switch as we go along; the EMBER-4 trial is looking at that switching approach? Dr. Nancy Davidson: Yeah, I think that this is obviously the billion-dollar question for many companies and for many of us as investigators. I don't know that I have a crystal ball into what the best approach might be. We know that already some of these have been abandoned. For example, amcenestrant. So, I don't even have to learn how to say it because it has been abandoned. It did go to phase 3, as you pointed out, in the advanced setting, looking at it with palbo vs letrozole plus palbo, and it didn't really show a whole lot that the company wanted to pursue. So, I think that sometimes these things are going to be abandoned based on the metastatic setting, which is a large trial, and that's a trial where obviously it might be a little easier to the circulating markers, as you talked about, than maybe in the early-stage breast cancer setting. I think that probably these early-stage trials are going to end up being big; they're going to have be clean. I'm guessing that most companies and most investigators will want to target them towards high-risk individuals, as you talked about, for 2 reasons. One is that ethically, I think we feel more comfortable with that. These are individuals where standard therapies are maybe not serving them as well as we would like and where we have information to think that we can at least have equipoise about a new approach. And the second is that from a trial design point of view, the event rate is likely to be higher, and therefore you might get answers earlier and with a smaller clinical trial. So that's where I suspect we're going to go. But it's a challenging question, and I think that many investigators and many companies are really trying to struggle with that right now because we do have so many options. And we're not quite sure how to, first, develop these new drugs, but then really importantly, put them in the context of our existing drugs. And as you say, we're also simultaneously trying to develop superior molecular or circulating markers to guide us. So, there's so many variables that are going on right now in this field that, from my point of view, itmakes it really exciting, but it also makes it pretty complicated, both for investigators and for pharma as we try to think about how to position these going forward. But what a great problem to have, Hope, because remember when you and I started in breast cancer, pretty much all you needed to know was tamoxifen. And I think you and I also probably started at the tail end of the time when we were using androgens and progestins and agents that now have basically completely fallen out of favor. Dr. Hope Rugo: Estrogen Dr. Nancy Davidson: Estrogen, yeah, and your side effect profiles were not as good. So, it's a good problem to have. It's a nice situation when science can inform our clinical investigation, our clinical practice. Dr. Hope Rugo: Yes, I think it'll be fascinating to see where we end up at the end, but of course, the complexities of this include the fact that sometimes just the clinical trial design leads to a less than positive result because of the way the trial itself has been designed, which I think is the nice part about moving these earlier into treatment of high-risk disease, but also brings up the question of all sorts of areas we're not really a place to discuss today, like how the statistical design is made, et cetera, that can sometimes result in poor evaluation of excellent agents. One of the questions that comes up, and you brought this up earlier, which I think is really important, is that we are in the era of combining our endocrine agents with targeted agents, and, oral agents, in a fascinating way, really bring up drug-drug interactions in a way that the injectable fulvestrant hasn't, and aromatase inhibitors were kind of quiet on the impacting metabolism, unlike tamoxifen. But we are seeing some drug-drug interactions and certainly the discussions about using these agents may include the question about whether or not you're having more diarrhea or nausea or fatigue or one drug causes photopsia, flashing lights, things like that. Keratitis is becoming a new toxicity to follow. How are we going to figure out how to sequence these drugs and are they only going to work better all of them as a class in patients with ESR1 mutations in their tumors? Dr. Nancy Davidson: I think we don't know the answer to the second question yet. That's something that really needs to be sorted out. Even if they do, that's still a really important subset of patients, assuming that we continue to start with the aromatase inhibitors, right? That's where those things really seem to emerge right now. I don't know how we're going to figure those things out. I guess that I'm hoping that maybe a couple of agents in these classes will become kind of the lead agents. And so, we'll be able to do this work with a handful of things as opposed to a whole array of things. But we'll see. I think that even within classes, obviously, these agents are going be slightly different, probably. And so it may be that one member of a class may be slightly better from a, maybe not from an efficacy point of view, but from a toxicity point of view. And we'll just have to see how it goes. I don't think I have any magic answers about that. Dr. Hope Rugo: Yes, it'll be interesting to see whether or not the agents work in sequence too. You know, could you use a PROTAC after an oral SERD, for example, or a CERAN? That'll be fascinating to see. Dr. Nancy Davidson: I'm hoping that preclinical modeling may help with that a little bit, though of course we all know that there are plenty of things that do well in preclinical models, GEMS and rodent models and PDXs, and sometimes those things translate nicely into clinical practice, but sometimes they don't. Dr. Hope Rugo: You mentioned, Nancy, that when we started out, that it was a fairly simple decision about what endocrine therapies, and we ran out very quickly. We're seeing some of those old classes come up with new agents. And you mentioned lasofoxifene, the oral SERM that seems to have some benefits and works in the later-line setting and also can be combined with a CDK4/6 inhibitor; [and also] has data with abemaciclib. There's also a new androgen receptor agonist, enobosarm, that's being tested as well. Do you think that these older mechanisms have a future as well? Dr. Nancy Davidson: I do. I think that because we'll be able to understand the biology better than we did in the past. A lot of our hormone therapy was pretty empiric several decades ago. But I think with better understanding of mechanisms and better understanding of what the patterns of resistance might be for a particular tumor, that we might be able to think about those things. You're right that there's a whole parallel universe right now in androgen receptor targeted therapies that we're not talking about today, both in perhaps in hormone-responsive breast cancers, but also in triple-negative breast cancers in a certain subset. And so that's an area where we probably need to be watching what our prostate cancer colleagues are doing as they develop these agents and thinking about where they might mechanistically make sense to apply in the breast cancer field. It won't be the first time that we've received insights from them because remember, prostate cancer people knew about androgen receptor mutations a really long time before we figured out that they existed in estrogen receptor as well. So, there's a nice cross talk, I think, between the prostate cancer field and the breast cancer field in that regard. Dr. Hope Rugo: That's an excellent point. And we learn a lot from our colleagues studying other malignancies, and prostate cancer has been a big area there for us and hopefully will help us with studying these agents because there's different toxicity profiles, of course, as well. And then you mentioned the approval of elacestrant, the first oral SERD to have regulatory approval, and it's approved in patients who have ESR1 mutations in their tumors. We're also studying it in the ELEVATE trial in combination with all of the different targeted agents, the CDK4/6 inhibitors, mTOR inhibitor, everolimus, and the PI3 kinase inhibitor, alpelisib, to really try and understand how these can be optimally combined. Would you check for ESR1 mutations at diagnosis of metastatic disease, or would you do this more after progression or start of progression of disease on an aromatase inhibitor? Dr. Nancy Davidson: I tend to be a conservative, Hope, and so unless there's a clinical trial that might be able to be considered, I would tend to check it only after progression on the aromatase inhibitor. But I think some people are earlier adopters, and I suppose it's possible that they might want to know from the get-go. Having said that, I do think elacestrant has an approval after aromatase inhibitor, as I recall. So, presumably the patient would have to have that exposure before you would be able to act on the ESR1 mutation by administering the oral SERD. This is also a new area that may well change with time, right? You know, as we develop different agents, as the agents have different requirements or different indications, and as we perhaps have better tests, it may be things that we don't do routinely now will become very routine in the future. And perhaps in series like you talked about in a serial fashion. Dr. Hope Rugo: Absolutely. I think that's a really important comment about how we're going to think about treating hormone receptor positive disease and potentially, you know, we have new chemo options, of course, not part of our talk discussion today and antibody drug conjugates. So, the future is certainly challenging in terms of understanding this appropriate sequencing. We need data, but it's exciting to have these options. As you pointed out, this is this is a great problem to have, you know, too many drugs with efficacy to try and understand how to use these in the most appropriate way. And as you also pointed out, the use in young women is particularly important. Whether or not you need to suppress the ovaries with all of these new agents is going to be important to understand as well as a next step. I don't know if you have specific thoughts on that area as well. I mean, that may reduce toxicity for younger women. Dr. Nancy Davidson: I guess our approach right now has been to suppress them, but I agree with you; you wonder if you look at some of the mechanisms of action, whether that's really a requirement biologically and medically, or whether it's something that's kind of a leftover from the approval process. You know, that for the drug approval, these women were suppressed. I think we need to work that out because that's another area where certainly women could have ovaries removed. That's pretty straightforward, although it requires a surgical procedure. But otherwise use of LHRH agonists continues to be injections, right? And so, if we're trying to minimize convenience or maximize convenience and minimize toxicity for women with any stage of breast cancer, anything we can do, it seems to me to eliminate an injection is going to be a good thing. So important for us to be able to work that out as well, even though numerically it's a smaller number of women, it's obviously a very important number. population of women. Dr. Hope Rugo: Last question for you. One question that comes up and sent to me and panels all the time is, if you have done your next generation sequencing and you see an ESR1 mutation and a P13CA mutation, what do you prioritize in terms of your choice of treatment, because we have the choice of either using elacestrant or a fulvestrant in combination with an agent targeting the PI3 kinase pathway? Dr. Nancy Davidson: I don't know that there's a right answer to that medically right now. So, when I talk about it with patients, I suggest to them that it's probably not one or the other. It's kind of the question of which one to use first. So, we talk a little bit about side effect profiles. We talk a little bit about patient preference and neither of these drugs is devoid of problems, but sometimes patients have pretty strong feelings about which set of side effects seems the least unattractive to them or the possibility of having those side effects. And I know that if one isn't well tolerated, you can swap over to the other. Dr. Hope Rugo: Absolutely. I think that's a very important way to think about next therapies in our era of not really knowing what's right. And this idea of shared decision-making is so incredibly important. Nancy, thank you so much for sharing your insights and knowledge with us today. I could talk to you for hours about this. Dr. Nancy Davidson: Hope, thank you so much for the opportunity. It is an exciting area and I really enjoyed talking with you about what we know and the many things that we don't yet know, but we're working on. Dr. Hope Rugo: Indeed, it's certainly an exciting time. Thank you to our listeners for joining us today. And thanks to the ASCO Daily News Podcast for highlighting this important area. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks 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. Follow today's speakers: Dr. Hope Rugo @hoperugo Dr. Nancy Davidson Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Hope Rugo: Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc Travel, Accommodations, Expenses: Merck, AstraZeneca Dr. Nancy Davidson: No Relationships to Disclose
Ústrednou témou tohto rozhovoru bolo, ako sa tu na to všetko nevysrať. A lepšieho hosťa ako Luciu Paškovú sme ani nemohli osloviť. Okrem toho, že založila slovenský Curaprox sa jej meno spája s projektami ako Kto pomože Slovensku, Kto pomôže Ukrajine, Bystriny, Nexteria alebo aktuálne Zapni sa pre Slovensko. Lucia je symbolom spájania sveta biznisu s neziskovým sektorom a je zároveň aj mama. Má 4 deti, 2 vlastné a 2 získala vrámci jej fungujúcej patchworkovej rodiny. Je vám asi jasné, že s Luciou by sa dalo rozprávať na nekonečne veľa tém. My sme sa snažili zistiť, čo je za tým, že je také aká je. A tiež spoznať ako funguje ako mama, ako na sebe pracuje a čo je za tým, že stále verí, že Slovensko je krajinou, v ktorej chce zostať a vychovávať svoje deti. V úvode podcastu vám predstavíme benefity od Unionu. Táto spolupráca nám totálne sadla. Okrem toho, že majú nový príspevok na Pampersky a Hipp, majú aj kopec ďalších benefitov, ktoré sa vám budú páčiť určite rovnako ako nám. Tu nájdete viac informácií o nových príspevkoch na plienky Pampers a vybrané produkty Hipp.
"Žiadna súdna reforma neprebehla. Nebola žiadna reforma pripravená. Bola pripravená, slušne povedané súdna reorganizácia, alebo neslušne, škatule hýbte sa. Imituje sa reorganizácia súdov, aby sa vybralo 250 miliónov z plánu obnovy. Ten chaos je veľký," hovorí sudca krajského súdu v Bratislave Peter Šamko, ktorého nedávno zvolili do Súdnej rady. "Vôbec by som spotrebnú držbu marihuany nekriminalizoval. Ak to chce mať štát ako protiprávne konanie, nech to presunú do priestupkov. Máte 17 ročných chlapcov, ktorí na Kolibe fajčia jointy, a policajti ich zoberú, za každého jedného majú čiarku za vznesené obvinenie, štatisticky sa to vykáže ako drogová kriminalita a máte zničené životy," komentuje sudca Šamko novelu trestného zákonníka v parlamente. Ako sa pozerá na kritiku, že by mal byť zdržanlivý? Čo by chcel dosiahnuť ako nový člen Súdnej rady? Ako sa pozerá na dedičstvo Štefana Harabina? A ako teraz v praxi vyzerá súdna reforma na súdoch? Pozrite si rozhovor Zuzany Kovačič Hanzelovej so sudcom Petrom Šamkom. Newsletter Zuzany Kovačič Hanzelovej: https://komentare.sme.sk/t/9122/zkh-pise – Ak máte pre nás spätnú väzbu, odkaz alebo nápad, napíšte nám na podcasty@sme.sk – Všetky podcasty denníka SME nájdete na sme.sk/podcasty – Podporte vznik podcastu Rozhovory ZKH a kúpte si digitálne predplatné SME.sk na sme.sk/podcast – Odoberajte aj denný newsletter SME.sk s najdôležitejšími správami na sme.sk/suhrnsme – Ďakujeme, že počúvate podcast Rozhovory ZKH
1. Tu ide o strany, nie o celok. 2. Chceli pomôcť hotovosti, ale len ju diskreditujú. 3. Pellegrini vystupuje z komfortnej zóny.
Recording from a farm in Paso Robles, Katerina is joined once again by her cousin Veru. It has been a year since Veru has been on the podcast and she is ready to share more about her first year and a half in the US. Veru compares how her life has changed from living a busy city life in Prague, Czech Republic to learning to slow down in California. They discuss the importance of having a good support network when you move through different chapters of your life and Veru shares what advice she would have told her younger self about moving to the US. Mentioned: Ep. 23 - Building a new home in a new culture with cousin Veru (last year's episode) Paso Robles Farm Airbnb Sculpterra Winery Cass Winery (for lunch) Ep. 51 - Sister from another mister with friend Julia Ep. 66 - Defining the role of a General Contractor with Jesse Subscribe to the From the Honeycomb newsletter! Meditate with Katerina on Insight Timer Honeycombee Blog Follow me on Instagram! Podcast Audio edit by Ma. Charmaine Sarreal, Podcast Specialist @iamchasarreal Intro music provided by kabgig / Pond5 By accessing this Podcast, I acknowledge that the entire contents are the property of Katerina Burianova, or used by Katerina Burianova with permission, and are protected under U.S. and international copyright and trademark laws. Except as otherwise provided herein, users of this Podcast may save and use information contained in the Podcast only for personal or other non-commercial, educational purposes. No other use, including, without limitation, reproduction, retransmission or editing, of this Podcast may be made without the prior written permission of the Katerina Burianova, which may be requested by contacting honeycombeeblog@gmail.com This podcast is for educational purposes only. The host claims no responsibility to any person or entity for any liability, loss, or damage caused or alleged to be caused directly or indirectly as a result of the use, application, or interpretation of the information presented herein.
Přidej se k The Tapes komunitě na herohero.co/thetapes pro epizody s předstihem a v plné délce, bonusy, tipy, Q&As, epizody navíc a další! Poslední epizoda s Veronikou, zakladatelkou projektu Systers.bio, měla obrovský úspěch a dnes bychom na ni volně navázaly s tématem, které do biohackingu taky hodně zasahuje a to doplňky stravy
Představuji vám Veroniku Petrás! Artistku permanentního make-upu, která mi tetuje obočí, ale hlavně podnikatelku, maminku, organizátorku světové soutěže permanentního make-upu WULOP pro Českou a Slovenskou republiku, organizátorku konference SKYPERMANENT a úžasnou žena, která se nám otevřela nejen ohledně tetování obočí, ale hlavně taky ohledně podnikání v kombinací s mateřstvím, psychiky a vyhoření. Moc si Tě cením, děkuju za krásnou epizodu Veru!Příjemný poslech!Veroniky Instagram: https://www.instagram.com/lamajja.veronikapetras/Veroniky webová stránka: https://lamajja.cz/Magic Academy Newsletter: https://www.magicacademy.cz/newsletter/Web Magic Academy: https://www.magicacademy.cz/Instagram Magic academy: https://www.instagram.com/magicacademy_cz/VIP members only: https://herohero.co/followyourmagic
"Mne sa strašne páči tento naratív. Keď nie je nič, tak všetci hovoria urobme. A ak navrhneme, tak hovoria, že to vždy nie je dosť. Dosť nebude mať nikdy nikto ničoho v tejto krajine. Človek má neobmedzené očakávania v každom smere. Je to krok pozitívnym smerom, naozaj reaguje na mnohé životné situácie a myslím, že je to dobrý, vecný návrh," hovorí dočasne poverený minister spravodlivosti Viliam Karas o kritike queer ľudí, že jeho návrh neupravuje ani dedenie. "Nie som nejaký politológ, ale účasť bola z môjho pohľadu významná. Je tu jasný signál od občanov, že majú predstavu, aby sa veci spravovali inak," komentuje účasť na referende minister Karas. Rozumie, že pre niekoho môže byť návrh o dôverníkovi u notára ponižujúci? A prečo nerieši zákon dedenie párov rovnakého pohlavia? Ako sa pozerá na ďalšie použitie paragrafu 363 pri poslancovi Borguľovi? A čo hovorí na výsledky referenda? Vypočujte si rozhovor Zuzany Kovačič Hanzelovej s dočasne povereným ministrom spravodlivosti Viliamom Karasom. – Newsletter Zuzany Kovačič Hanzelovej: https://komentare.sme.sk/t/9122/zkh-pise – Ak máte pre nás spätnú väzbu, odkaz alebo nápad, napíšte nám na podcasty@sme.sk – Všetky podcasty denníka SME nájdete na sme.sk/podcasty – Podporte vznik podcastu Rozhovory ZKH a kúpte si digitálne predplatné SME.sk na sme.sk/podcast – Odoberajte aj denný newsletter SME.sk s najdôležitejšími správami na sme.sk/suhrnsme – Ďakujeme, že počúvate podcast Rozhovory ZKH.
Referendum, ktoré iniciovali opozičné strany na čele so Smerom-SD síce nebolo úspešné, no podľa politológa Erika Láštica výsledok ukazuje, aké majú opozičné strany silne jadro voličov. „Východisková pozícia je pre súčasnú opozíciu veľmi dobrá. Výsledok referenda sa nedá vysvetliť inak, než ako výrazné varovanie pre strany či už súčasnej vládnej koalície alebo tie, ktoré ju tvorili v roku 2022," hovorí v podcaste politológ Erik Láštic. Bývalí koaliční lídri sa zároveň cez víkend dohodli na termíne predčasných volieb - na september. „Vnímam celkom problematicky, ako sa k tomu postavili strany bývalej koalície. Nie sú schopné vytvoriť novú funkčnú väčšinu, ale chcú zostať vo funkcii do konca septembra. Je to pomerne dlhá doba. Viem si živo predstaviť, že keby takáto situácia nastala napríklad počas tretej vlády Roberta Fica, tak by opozícia hnala ľudí na námestia,“ myslí si tiež Erik Láštic. Septembrové voľby môžu podľa politológa znamenať obrovskú výzvu pre súčasné vládne strany, aby sa priblížili poslednému výsledku vo voľbách alebo sa vôbec do parlamentu dostali. No otvára to dvere aj novým projektom. „Môže to byť šancou, súčasne aj rizikom pre iné strany - či tie, ktoré sú mimo parlamentu alebo pre zoskúpenia, o ktorých sa diskutuje a mali by ponúknuť alternatívu vládnej koalícii, ale aj opozíci." Generálny prokurátor Maroš Žilinka minulý týždeň cez paragraf 363 zrušil obvinenie poslancovi Martinovi Borguľovi. V druhej téme podcastu sa s novinárkou Aktualít Laurou Kellöovou pozrieme na to, ako to generálny prokurátor zdôvodnil v uznesení. Podcast pripravili Denisa Hopková a Denisa Žilová.
Referendum, ktoré iniciovali opozičné strany na čele so Smerom-SD síce nebolo úspešné, no podľa politológa Erika Láštica výsledok ukazuje, aké majú opozičné strany silne jadro voličov. „Východisková pozícia je pre súčasnú opozíciu veľmi dobrá. Výsledok referenda sa nedá vysvetliť inak, než ako výrazné varovanie pre strany či už súčasnej vládnej koalície alebo tie, ktoré ju tvorili v roku 2022," hovorí v podcaste politológ Erik Láštic. Bývalí koaliční lídri sa zároveň cez víkend dohodli na termíne predčasných volieb - na september. „Vnímam celkom problematicky, ako sa k tomu postavili strany bývalej koalície. Nie sú schopné vytvoriť novú funkčnú väčšinu, ale chcú zostať vo funkcii do konca septembra. Je to pomerne dlhá doba. Viem si živo predstaviť, že keby takáto situácia nastala napríklad počas tretej vlády Roberta Fica, tak by opozícia hnala ľudí na námestia,“ myslí si tiež Erik Láštic. Septembrové voľby môžu podľa politológa znamenať obrovskú výzvu pre súčasné vládne strany, aby sa priblížili poslednému výsledku vo voľbách alebo sa vôbec do parlamentu dostali. No otvára to dvere aj novým projektom. „Môže to byť šancou, súčasne aj rizikom pre iné strany - či tie, ktoré sú mimo parlamentu alebo pre zoskúpenia, o ktorých sa diskutuje a mali by ponúknuť alternatívu vládnej koalícii, ale aj opozíci." Generálny prokurátor Maroš Žilinka minulý týždeň cez paragraf 363 zrušil obvinenie poslancovi Martinovi Borguľovi. V druhej téme podcastu sa s novinárkou Aktualít Laurou Kellöovou pozrieme na to, ako to generálny prokurátor zdôvodnil v uznesení. Podcast pripravili Denisa Hopková a Denisa Žilová.
HÆ hæ Live Show verður 17. Nóvember í Sykursal hjá Mathöll Veru. Þemað: Sambönd eða single?Þetta er stóri bílaþátturinn. Hjálmar rústaði bílnum sínum þegar hann var nýkominn með bílpróf. Helgi hefur aldrei keyrt á neinn nema að láta vita af því. Hvað má og má ekki gera í búningsklefa í leikskólum? Þættina má finna inni í áskrift á pardus.is!IG: helgijean & hjalmarorn110 Takk fyrir að hlusta - og munið að subscribe'a!
HÆ hæ Live Show verður 17. Nóvember í Sykursal hjá Mathöll Veru. Þemað: Sambönd eða single?Ef HÆ hæ myndi eignast barn hvað myndi það heita? Hvað myndi Ágústa vilji mikinn pening fyrir að heita Hrágústa Majones Skinka?Hvað eru skrítnustu veislurnar?IG: helgijean & hjalmarorn110 Takk fyrir að hlusta - og munið að subscribe'a!
HÆ hæ Live Show verður 17. Nóvember í Sykursal hjá Mathöll Veru. Þemað: Sambönd eða single?Eyþór Atli úr hlaðvarpinu Hver er Húgó? kíkti til okkar í gott spjall. Eyþór og Hjálmar ásamt öðrum kíktu saman til London í sumar. Þar upplifðu þeir hin ótrúlegustu ævintýri. Þættina má finna inni í áskrift á pardus.is!IG: helgijean & hjalmarorn110 Takk fyrir að hlusta - og munið að subscribe'a!
HÆ hæ Live Show verður 17. Nóvember í Sykursal hjá Mathöll Veru. Þemað: Sambönd eða single?Beggi Ólafs fyrirlesari, hlaðvarpsstjarna og rithöfundur kíkti í spjall til okkar í dag. Hann tók fyrir reglur sem fólk getur nýtt sér á lífsleiðinni og sagði einnig frá nokkrum vandræðalegum augnablikum.IG: helgijean & hjalmarorn110 Takk fyrir að hlusta - og munið að subscribe'a!
HÆ hæ Live Show verður 17. Nóvember í Sykursal hjá Mathöll Veru. Þemað: Sambönd eða single?Helgi lenti í svakalegu fyllerýi í næturlest frá Prag til Krakow.Hjálmar hringdi í Hagkaup sem Páll Óskar. Hver er rétti tíminn til að ferðast erlendis? Hjálmar hringdi í DeCode og vildi athuga hvort hann væri í alvörunni með lélega tónheyrn. Þættina má finna inni í áskrift á pardus.is!IG: helgijean & hjalmarorn110 Takk fyrir að hlusta - og munið að subscribe'a!
Episode 207: In this screen-share, Adam Gefvert, the head analyst from White Diamond Reseach goes over the latest part of a series of short reports unveiling the many problems of Veru Pharma. [NASDAQ: VERU]Full Short Report: https://whitediamondresearch.com/research/part-2-new-red-flags-emerge-from-verus-phase-3-covid-trial-suggesting-an-fda-rejection-is-likely/ Social mediaDavid CapablancaTwitter: reverse_longInstagram: reverselong
Veronika Allister je mou hostkou již potřetí. Není divu. Je tolik témat a otázek, které mi leží na téma jejího zaměření na srdci, že by vydali na celou sérii. Veru se věnuje biohackingu, konkrétně se zaměřuje na dlouhověkost žen. Proč? Ženy a muži jsou, jde-li o tělo a jeho principy, do jisté části odlišní. Výzkumů a studií zaměřených na kvalitu a délku života žen je pomálu. Nicméně zájem o téma roste a s ním i tato oblast. Tento rozhovor jsem primárně zaměřila na ženy, na vaginální mikrobiom, protože dámy a pánové, to je jinej svět! Povídaly jsme si o tom, jak se starat o naší intimní zahrádku, jak vzniká vaginální dysbióza a jak jí předcházet. Odtud jsme přešly k tématu menstruace, menstruačnímu cyklu a jeho měření a tématu cervikálního hlenu. Celým podcastem se nese téma biohackingu jako takového. Proto jsem na úvod Veru poprosila o sdílení dojmů z návštěvy Biohacker Summitu v Helsinkách. Závěr podcastu se nesl v duchu vztahů, protože právě vztahy se ukazují býti jednou z nejdůležitějších skládaček spokojeného a dlouhého života. Proto mě zajímalo, jak se daří právě Veru pečovat o ty své, konkrétně o vztah s jejím mužem, a jaké jsou podle ní základy zdravého harmonického vztahu. Přeji příjemný poslech. V BONUSové části jsme se věnovaly tématu doplňků stravy. Proč je potřeba je v dnešní době brát, jak začít? Více zde: https://herohero.co/nastavdusi Veronika Allister BLOG Systers.bio: https://www.systers.bio/blog/ SYSTERS kempy: https://www.systers.bio/eventy/ BROTHERS. kempy: https://allister.cz/brothers-camp/ ALLISTER festival pro páry: https://allister.cz/allister-festival/ --- Send in a voice message: https://anchor.fm/nastavdusi/message
#100 Silný výber – PRVÝ JUBILEJNÝ DIEL! Trvalo to viac ako tri roky, ale je to tu. 100. (sic!) Silného výberu. Verím, že oslávite spolu s nami toto naše jubileum - keď už nijak inak, tak tak, že nás za vervu, zápal a nasadenie, s ktorým vás už viac ako tri roky zabávame - konečne zazdieľate:-). Silný výber. Sto dôvodov, prečo sa oplatí počúvať na slovo:-)! Pripíjame a pripomíname: Romana, Gabriel, Xanďo, Tony Jašík, 8. výročie založenia WiU - Conflict Intelligence Team - a pozor v rámci súťaže Dedina roka - striebro pre Kocurany! Jo a naša stovka - obrovská vďaka redakcii a všetkým poslucháčom! Historický kalendár Jána Žideka (výber) Ján Kuciak by 17. mája oslávil 32 rokov. V pietnej spomienke si pripomíname nedávno zosnulého českého herca Jozefa Abrháma. Pred 45 rokmi USA a ZSSR uzatvorili zmluvu o nepoužívaní chemických a biologických zbraní. 209 rokov od smrti skladateľa a dirigenta Richarda Wagnera. Podporiť nás môžete aj takto: https://www.paypal.com/paypalme/volebnanoc https://www.paypal.com/paypalme/slavomirolsovsky?country.x=LU&locale.x=en_US Endorse: Jubileum nemáme len my, ale aj naše obľúbené knižné vydavateľstvo Inaque, ktoré má 10 rokov (čiže len o nulu menej ako my:-))): https://inaque.sk/edicia/cygne/ Vypočujte si aj naše ďalšie podcasty: Kunstkamera: https://kunstfilter.podbean.com/ Hybadlo: https://hybadlo.podbean.com/ Hudba v podcaste: George Gershwin – Rhapsody in Blue Odporúčaná hudba: Ногу Свело! – Назад, Россия! https://www.youtube.com/watch?v=3EhcakGH7po Kozak System – Мamo https://www.youtube.com/watch?v=9DMw_XwQcVE
Flywire (FLYW) stock price was up over 5% today. Recently, SMBC Nikko started the Flywire (FLYW) stock at an outperform rating and a $40 price target. How does FLYW compare to SQ, STNE, and PYPL? Next, George Tsilis discusses Veru Inc. (VERU), an oncology biopharmaceutical company as their Covid-19 drug candidate shows a 55% death reduction in hospitalized patients during a phase 3 study.
In this episode, Jon talks with Pete Veru, guitarist in the band "Feather Merchants", about music and Pete's interesting careers. connvalley.net
Dělat rozhovor s Veronikou Kašákovou, je jak jít na příjemné kafe s kamarádkou. Slzy dojetí střídalo vyprávění o tom, co nás na mateřství nejvíc překvapilo, čeho se bojíme, co nejvíc milujeme a jak mateřství (ne)naplnilo naše očekávání. Veru je anděl, který toho má tolik na srdci a z jejího klidného povídání se můžete inspirovat nejen v pohledu na mateřství, ale i v tom, jak se snaží vést svého syna k udržitelnosti, v čem obě máme velké mezery a co bychom si přály zlepšit. Děkujeme za krásnou příležitost a za spolupráci se značkou HIPP, která vám tento díl podcastu přináší.