Podcasts about HIF

Nytt avsnitt av podden med Anders, Håsan och Jens. Örgrytematchen, Max Mölders eventuella sommar-exit och potentiella ersättare till honom samt uppsnack inför måndagens derby mot HIF.  Heja BoIS!

Avsnitt 475 av Sveriges nyfiknaste fotbollspodd gästas av Mattias Lindström. Tränaren talar om att lämna Degerfors efter att ha varit med och tagit upp klubben i allsvenskan, om valet att kliva ner i division 1 igen, om att träna spelare som jobbar vid sidan av fotbollen, om misstagen han gjorde senast på denna nivå, om fotbollen han vill se, om ambitionerna hos Ariana, om växtvärken hos Malmö-klubben och om målet att nå allsvenskan.Dessutom berättar Lindström om valet att satsa på en tränarkarriär, om oron över att poddandet gjort att han inte framstår som seriös, om varför det gick bra i Tvååker, om vad som gick snett i Eskilsminne, om stoltheten över att bli assisterande i Helsingborgs IF, om att det gick för snabbt uppåt för klubben, om de tuffa tagen när han själv var huvudtränare, om vad som gått fel i HIF på senare år och om när klubben kan vara tillbaka i allsvenskan. Hosted on Acast. See acast.com/privacy for more information.

In this JCO PO Article Insights episode, host Harold Tan summarizes Low Kynurenine Levels Among Exceptional Responders on Phase Ib Trial of the HDAC Inhibitor Abexinostat with Pazopanib by Tsang et al, published November 07, 2024. Transcript Harold Nathan Tan: Welcome to JCO Precision Oncology Article Insights, where we explore cutting-edge discoveries in the world of cancer treatment and research. I'm Harold Nathan Tan, your host, and today we're taking a focused look at a compelling phase Ib trial led by Dr. Tsang, which investigates a combination of abexinostat, a histone deacetylase inhibitor, with pazopanib, a VEGF-targeting tyrosine kinase inhibitor, in patients with advanced solid tumors. VEGF inhibition has long been an established therapeutic strategy across a wide range of tumor types, including colorectal, ovarian, sarcoma, and renal cell carcinoma. These agents function by disrupting tumor angiogenesis, effectively limiting oxygen and nutrient delivery to malignant cells and contributing to improved survival outcomes. However, over time, acquired resistance remains a significant challenge. A key mechanism implicated in this resistance involves the upregulation of hypoxia-inducible factor 1-alpha, or HIF-1-alpha for short, a master regulator of angiogenesis that restores VEGF signaling under hypoxic conditions. Interestingly, HIF-1-alpha overexpression is mediated by histone deacetylases, especially HDAC2. Preclinical studies suggest that HDAC2 inhibition can suppress tumor cell migration and downregulate HIF-1-alpha activity, effectively disabling a critical escape pathway used by tumors under VEGF pressure. Moreover, combining HDAC inhibition with VEGF blockade has demonstrated synergy in pazopanib-resistant tumor models, forming a compelling rationale for this dual approach. The phase Ib trial by Tsang et al. was designed to evaluate the safety, tolerability, and preliminary efficacy of this dual-targeted approach in patients with heavily pretreated advanced solid tumors. A dose-expansion cohort focused on individuals with renal cell carcinoma, allowing for more detailed evaluation in this population. A central component of this study was the incorporation of biomarker analysis, particularly regarding HDAC2 expression levels. The results were noteworthy. Patients with high HDAC2 expression achieved a progression-free survival of 7.7 months compared to only 3.5 months in those with low expression. Even more compelling, overall survival reached 32.3 months for those with a high HDAC2 expression versus just 9.2 months for those with low expression. This suggests the potential role for HDAC2 as a predictive biomarker for response to combination HDAC and VEGF-targeted therapy. The authors also explored the metabolic landscape of these patients, conducting metabolomic analysis focused on kynurenine, a key tryptophan catabolite known to contribute to the immune suppression in the tumor microenvironment. Its reduction is driven by HIF-1-alpha and inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. What they found was striking. Exceptional responders, defined as patients with treatment responses lasting more than 3 years, had consistently lower levels of kynurenine both before and after treatment. This finding introduces kynurenine as a potential metabolic biomarker. It suggests that patients with lower kynurenine levels may have a less immunosuppressive microenvironment, making them more responsive to the combined effects of HDAC inhibition and VEGF blockade. Of note, VEGF levels themselves did not significantly differ between responders and nonresponders, highlighting that the treatment benefit is not purely VEGF-mediated but likely driven by epigenetic and metabolic modulation. On the safety front, the combination of abexinostat and pazopanib was generally well tolerated. However, this study did report a correlation between higher plasma concentrations of abexinostat and an increased incidence of thrombocytopenia, a class effect associated with HDAC inhibitors. This trial introduces several key considerations for future research. First, it calls for validation of HDAC2 as a predictive biomarker. If confirmed in larger cohorts, HDAC2 expression could be used to select patients most likely to benefit from HDAC inhibitor-based regimens, transforming how we approach trial enrollment and treatment planning. Second, the link between low kynurenine and exceptional response supports further investigation into how metabolic pathways can influence treatment response to combined HDAC and VEGF inhibition. Overall, HDAC inhibitors hold significant promise in precision oncology. Realizing their full therapeutic potential requires a deeper understanding of HDAC biology, refined combination strategies, and thorough preclinical and clinical evaluations tailored to individual patient profiles. This study exemplifies the potential of epigenetic-metabolic crosstalk as a therapeutic vulnerability and underscores the importance of precision stratification in clinical trial design. As research in this space progresses, the integration of molecular, epigenetic, and metabolic profiling will be essential in optimizing the use of HDAC inhibitors and expanding their role within precision oncology. Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.   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.

De träffades för första gången på ungdomslandslagsläger när de var 15 år. Deras vägar korsades igen många år senare på Olympia. Idag är Reda Chahrour och Mikael Dahlberg klubbdirektör respektive sportsligt ansvarig i HIF.I detta avsnitt berättar de bland annat om minnena av varandra från ungdomsåren, hur de arbetar ihop i vardagen, om beslutsprocesser, strategier och svarar på många av era frågor.

Avsnitt 470 av Sveriges nyfiknaste fotbollspodd gästas av Jordan Larsson. Anfallaren talar om att jaga nya pokaler med FC Köpenhamn, om krävande supportrar, om att hantera tuff konkurrens, om att för många stjärnor kostade titlar 2024, om att den danska storklubben är ett par steg upp från Malmö FF, om att aktiebolaget FCK satsar rejält och om känslan att FCK kan gå långt i Europa.Dessutom berättar Larsson om valet att satsa på fotbollen framför skolan, om relationen med en del personer i HIF, om Jens Gustafssons betydelse i IFK Norrköping, om den första succén i Spartak Moskva, om reaktionerna när han ensam gick ner på knä för Black Lives Matter, om rysk ilska när han bröt kontraktet efter kriget, om den fina tiden i AIK som fick honom att fundera på att stanna, om besvikelsen när Janne Andersson redan bestämt sig i EM och om hoppet att Jon Dahl Tomasson ska höra av sig. Hosted on Acast. See acast.com/privacy for more information.

The phase 3 LITESPARK-005 trial evaluated patient-reported outcomes (PROs) for belzutifan, a HIF-2α inhibitor, versus everolimus in patients with advanced renal cell carcinoma previously treated with immune checkpoint and anti-angiogenic therapy. 

Cristina Suárez analiza los próximos ensayos clínicos que podrían transformar el manejo del cáncer renal en los próximos años: nuevas combinaciones adyuvantes y estrategias perioperatorias, el uso de tripletes enprimera línea y la integración de inhibidores de HIF con TKIs, entre otros.

Featuring perspectives from Dr Thomas E Hutson, Dr Rana R McKay, Dr Sumanta Kumar Pal and Dr Tian Zhang, moderated by Dr Pal, including the following topics: Introduction (0:00) Immunotherapeutic Strategies for Localized and Metastatic Clear Cell Renal Cell Carcinoma (RCC) — Dr Hutson (2:34) Optimal Management of Relapsed/Refractory RCC — Dr Zhang (32:49) Role of HIF-2α Inhibitors in the Treatment of Sporadic and von Hippel-Lindau-Associated RCC — Dr McKay (1:04:02) Current and Future Care of Patients with Non-Clear Cell RCC — Dr Pal (1:33:13) CME information and select publications

Concluding the series on hypoxia inducible factor in skeletal muscle, we go in depth with a paper investigating regulation pathways that blunt HIF's effects in well trained athletes, plus speculate as to whether the Pasteur effect is something worth worrying about while considering other evidence and parallel adaptive pathways. We also ponder some practical takeaways for very well trained endurance athletes as well as for those earlier in their training career.

Målvakten Johan Brattberg gästar HIF Talk och berättar bland annat om sin första tid i HIF, hur han blev målvakt, ger en inblick i sin fotbollsresa och matlagningsintresse samt hur han lär känna sina nya lagkamrater under lägret.

This week on HIF player we discover how to get around to the things that count with Oliver Burkeman, recorded live at Berwins Salon North.  In this uplifting and liberating talk, Oliver Burkeman guides us towards building a more meaningful life in a bewildering era– how to get around to what counts in a world of anxieties and distractions. Addressing the fundamental questions about how to live, Oliver offers a powerful new way to take action: a guiding philosophy of life that he calls ‘imperfectionism'. Oliver's insight will be a source of solace and inspiration, and an aid to a saner, freer, and more enchantment-filled life. Podcast Music by Joseph McDade. 

HIF Talk återvänder och gästas av hemvändaren Max Svensson som bland annat berättar om tvivlen under tonåren, proffslivet i Nederländerna, och de svåra månaderna i Kalmar innan han vände hem till HIF. Dessutom om uppväxten, utvecklingen och träningslägret.

Toni Choueiri discusses the updated data from different cohorts of this novel HIF inhibitor.

This week on HIF player we learn all about connections with Nick Couldry, recorded live at Berwins Salon North.  In this compelling and urgent podcast, Nick Couldry argues that Big Tech is quietly seizing control over our most valuable resource – our personal data. This isn't just about privacy; it's about how your data is being used to shape your behaviour, your choices, and even your future. Nick explains how we ended up here and, more importantly, what we can do about it. Podcast Music by Joseph McDade. 

La renuncia el jueves pasado del presidente de Ancap, Alejandro Stipanicic, por diferencias con el Poder Ejecutivo, sigue despertando algunas preguntas. Un breve repaso. Este viernes 27 de diciembre, Alcoholes del Uruguay (ALUR) tiene previsto firmar un Acuerdo de Implementación con la empresa HIF Global. Esto para seguir avanzando con un proyecto de inversión de esa compañía de capitales chilenos en Paysandú, para instalar una planta que utilizará CO2 generado por ALUR e hidrógeno verde para producir combustibles sintéticos. Recordemos que, de concretarse, la planta de HIF supondría la mayor inversión en la historia del país: US$ 6.000 millones. El Acuerdo de Implementación debe firmarse antes de fin de año por una cuestión de plazos estipulados en el memorándum de entendimiento que se firmó con HIF en febrero, pero la decisión final sobre el proyecto se tomaría recién en mayo de 2026. Ahí se espera que el negocio en torno a este proyecto esté más claro, dado que hoy no existe demanda de combustible sintético.  ¿Por qué entonces tanta polémica ahora? Entre el presidente saliente del ente, Alejandro Stipanicic, y el Poder Ejecutivo, se abrió una diferencia referente a una cláusula del Acuerdo de Implementación, que le daba a Ancap la opción de participación a futuro en el proyecto. Cuando se tome la decisión final sobre la planta de HIF, Ancap podría tomar una participación hasta del 30% del negocio. Y si allí decidiera no participar, no tendría que pagar ninguna penalización. Stipanicic consideraba que era importante dejar esa opción abierta. Sin embargo, el Poder Ejecutivo exhortó al Directorio de Ancap a eliminar la cláusula en cuestión, y Stipanicic decidió renunciar a su cargo argumentando que no existía “ninguna razón técnica, económica ni jurídica” para seguir el camino ordenado por el gobierno. El sábado, en su cuenta de la red social X, el canciller Omar Paganini, quien fuera previamente ministro de Industria, publicó un texto afirmando que el gobierno pretende que la inversión de HIF siga adelante y la calificó como “una gran oportunidad para el país”. Pero aclaró que Ancap participa como proveedor de CO2 y no como inversor. “El proyecto de HIF no depende de que Ancap invierta. Cuenta con socios de Chile, EEUU, Alemania y Japón. Ellos están asumiendo la inversión y el riesgo, y Ancap obtendrá beneficios rentabilizando un subproducto. Es una situación de ganar-ganar”, escribió Paganini. El jerarca dijo que el monto de la inversión es demasiado alto, y el negocio demasiado incierto, como para que Ancap corra el riesgo. Recordó entonces los casos de Pluna y de la regasificadora, “que costaron muchos millones a los uruguayos”. “Los proyectos de Hidrógeno Verde no deberían ser otra regasificadora”, escribió Paganini. Continuó: “Una cosa es un proyecto con beneficios para Ancap y para los privados, y otra muy diferente es invertir fortunas de los contribuyentes y que por añadidura el Estado salga de garantía”. El canciller cerró diciendo que debe haber una “adecuada asignación de riesgos entre el Estado y los privados” y que “otra cosa son las aventuras con el dinero de todos”. Profundizamos En Perspectiva sore este tema con la actual ministra de Industria, Energía y Minería, la ingeniera Elisa Facio.

Jim Brugarolas joins to discuss his talk from IKCS 2024 and the board topic of resistance to HIF inhibitors.

Here we talk with Dr Shai Efrati about HBOT, Hyperbaric Oxygen Therapy and his protocol. It is counterintuitive but the mechanism is through the activation of HIF via hypoxia!

This week on HIF player we explore the most surprising events in recent years with journalist, writer and broadcaster Phoenix Andrews, recorded live at Berwins Salon North.  He sheds light on the fascinating world of fandoms and reveals how a passion wave of people power has become the hidden force behind the most surprising events in recent history – from the mass movements resulting in Brexit and Trump, culture wars and conspiracy theories, to online engagement that enriches lives and inspires positive social and political change. Podcast Music by Joseph McDade. 

A study knocking out HIF1alpha in mice reveals a counterintuitive relationship between markers of phenotype like fat oxidation, mitochondria markers, capillary density, and fiber type, and not having improved baseline performance. This uncovers an interesting relationship between the HIF pathway and oxidative metabolism, and how seemingly opposing adaptations are complementary.

Sam Jones and Isabel Vieira discuss the 70 year anniversary of private health insurer HIF. Plus, Major MinRes shareholder sells; Perth office vacancies fall; and Orthocell looks to the US market.

References Am J Physiol Cell Physiol 2019 Sep 1;317(3):C502-C512 Browne, J. 2002."Dont You Want to be There?" https://open.spotify.com/track/2e62rpQnEaVoQHWltXWDVV?si=8ba86ab27eeb4972 Simon, P. 1970. "The Boxer" https://open.spotify.com/track/76TZCvJ8GitQ2FA1q5dKu0?si=db43bb95e8504819 Biber, HIF von. 1681. Sonata 8 https://open.spotify.com/track/56hzAmdRl7ndN95YFeksUQ?si=0128734522544c1e --- Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

This week on HIF player we debunk the myths behind running with Allie Bailey, recorded live at Berwins Salon North. Named by The Guardian as “one of the most inspiring female adventurers in the UK”, ultrarunner, adventurer and endurance running and mindset coach Allie Bailey has finished over 200 marathons and ultramarathons and run in some of the most extreme places in the world. The most remarkable thing about all of her achievements, however, is that she accomplished most of them while battling depression and alcoholism.

IKT om tunga torsken mot Rangers och HIF-inslagen på bortaläktaren. Elfsborgs hedersamma förlust mot AZ och BP:s dystra form. Vi scannar av den kryssande bottenstriden och blickar mot kommande Stockholmsderby. Dessutom Kalmars pinne mot HBK - bra eller anus? Hosted on Acast. See acast.com/privacy for more information.

Behövs fler kapitel i playbooken? Och vem ska ersätta Max Nilsson? Här är avsnitt 97 av Landskrona BoIS-podden. Derbyförlusten mot HIF står i centrum när Mattias Hjälm och Sebastian Rönström tar plats i poddstudion. I veckans avsnitt diskuteras även följande ämnen: • Så kunde BoIS hotat HIF mer. • Problemen i sista tredjedelen. • Skandalscenerna på läktaren. • Dags att testa Capotondi. • Han sprang mest i derbyt. • Därför skrev Sebastian Rönström att Max Mölder har få taktiska övermän. • Billy Magnussons befriande uttalande. • Max Nilssons avstängning. Hur ska BoIS tackla mötet med Örebro?

Landskrona BoIS-podden är tillbaka och bjuder på ett fullmatat avsnitt. Den här veckan samtalar Mattias Hjälm och Sebastian Rönström kring följande punkter: • BoIS blev en vinnare trots 0–0 mot Öster, men var det verkligen seriens två bästa lag som möttes? • Max Mölders reaktion på presskonferensen. • Hur ska vi egentligen formera BoIS startelva? • Hemma- och bortatabellen som talar för BoIS mot Örgryte, men mot BoIS i derbyt mot HIF. • Victor Karlsson kontra Constantino Capotondi – varför får inte sommarens nyförvärv större utrymme? • Därför är BoIS en föregångare såväl sportsligt och organisatoriskt som på transfermarknaden. • BoIS kan kanske såga av HIF:s gren, och får gälla som favorit i derbyt. Men vad gör pressen med den unga och oerfarna truppen? • HIF-hotet som BoIS måste se upp med. • Han blir derbyhjälte – om Mattias Hjälm och Sebastian Rönström måste välja en.

Brad McGregor joins Brian and Tom to discuss a new HIF inhibitor, NKT2152, and preliminary data in RCC

Den (möjligen) historiskt dåliga insatsen mot Sandviken. HIF härnäst. Råskinn, psykfall, galning och alla andra synonymer som beskriver en lagkapten. Årets Jesper Dickman-värvning!   Intro- & Outrolåt: Audioscribe - Shimmer Tillgänglig hos: NoCopyrightSounds NoCopyrightSounds finns på Youtube och Spotify

At the 2024 Kidney Cancer Research Summit (KCRS), CancerNetwork® spoke with various experts in the kidney cancer field about potential advancements in disease detection and updated efficacy data on immunotherapy and other treatment strategies in patients with renal cell carcinoma (RCC). Karl Semaan, MD, MSc, a postdoctoral oncology research fellow at Dana-Farber Cancer Institute, discussed the implications of findings related to the use of an investigational tissue-informed liquid biopsy epigenomic profiling tool for detecting sarcomatoid differentiation in RCC.1 According to Semaan, this method may avoid the sampling errors and spatial heterogeneity challenges associated with traditional biopsy strategies. Additionally, Neil J. Shah, MBBS, an assistant attending physician from Memorial Sloan Kettering Cancer Center, spoke about data from a real-world study evaluating treatment patterns and outcomes in those with metastatic RCC following prior receipt of immunotherapy and tyrosine kinase inhibitors (TKIs).2 Data showed no differences in overall survival (OS) outcomes across different immunotherapy- and TKI-containing regimens. Based on these findings, Shah emphasized a need for additional novel therapeutic approaches to help improve outcomes in later-line settings of treatment. Bradley A. McGregor, MD, director of Clinical Research for the Lank Center of Genitourinary Oncology and medical oncologist specializing in genitourinary malignancies at Dana-Farber Cancer Institute, highlighted findings from his presentation on a phase 1b study (NCT04627064) evaluating treatment with abemaciclib (Verzenio) in a pretreated metastatic clear cell RCC population.3 Among 11 patients who received abemaciclib, 1 had stable disease, 8 had progressive disease, and 2 were not evaluable for response. Additionally, the median progression-free survival (PFS) and overall survival (OS), respectively, was 1.8 months (95% CI, 1.5-1.9) and 9.1 months (95% CI, 2.1-15.3). Although abemaciclib monotherapy yielded no responses in the study, McGregor highlighted the potential clinical utility of administering the agent in combination with other therapies. Findings from his presentation suggested that CDK4/6 inhibitors may demonstrate a synergistic effect when combined with HIF-2α inhibitors, which is a potential strategy that investigators are evaluating with belzutifan (Welireg) and palbociclib (Ibrance) combination therapy as part of the phase 1/2 LITESPARK-024 trial (NCT05468697). References 1.        Semaan K, Zarif TE, Eid M, et al. Liquid biopsy epigenomic profiling for the detection of sarcomatoid renal cell carcinoma. Presented at the 2024 Kidney Cancer Research Summit; July 11-12, 2023; Boston, MA. Abstract 44. 2.        Shah N, Sura S, Shinde R, et al. Real-world treatment patterns and clinical outcomes of metastatic renal cell carcinoma patients post immune-oncology (IO) and Vascular Endothelial Growth Factor (VEGF) receptor targeted therapies. Presented at the 2024 Kidney Cancer Research Summit; July 11-12, 2023; Boston, MA. Abstract 36. 3.        McGregor BA, Xie W, Xu W, et al. Phase IB trial of abemaciclib in advanced renal cell carcinoma. Presented at: 2024 Kidney Cancer Research Summit; July 11-12, 2024. Boston, MA.

Stay up-to-date on the latest advancements and treatment strategies in the field of genitourinary oncology. In this episode of BackTable Urology, guest host Dr. Bogdana Schmidt, a urologic oncologist from the University of Utah, discusses takeaways from ASCO 2024 with Dr. Petros Grivas from Fred Hutchinson Cancer Center and Dr. Sumanta (Monty) Pal from City of Hope. --- CHECK OUT OUR SPONSOR Siemens Healthineers Theranostics https://www.siemens-healthineers.com/en-us/clinical-specialities/theranostics --- SYNPOSIS The conversation initially focuses on advanced urothelial carcinoma and the EV302 trial, discussing detailed insights from the quality-of-life results presented at ASCO. The experts offer relevant clinical perspectives for modern metastatic urothelial carcinoma management, focusing on pembrolizumab plus enfortumab vedotin. Further, they delve into breaking biomarker research at ASCO, including KIM-1 in adjuvant renal cell carcinoma (RCC) therapy and the HIF-2 inhibitor DFF332 for chromophobe RCC. --- TIMESTAMPS 00:00 - Introduction 03:42 - Pembrolizumab and Enfortumab Vedotin Trial Insights 07:43 - Future Trials and Treatment Strategies 21:27 - Javelin Bladder 100 Trial Discussion 32:05 - Growth Factor Use 36:21 - Future Directions of Biomarkers 38:55 - Kidney Cancer Biomarker Trials 53:40 - Concluding Thoughts

Sollte es zu einer Abkehr vom Verbrennerverbot kommen, können die Klimaziele im Verkehr nur mit Hilfe synthetischer Kraftstoffe (E-Fuels) erreicht werden. Wie und zu welchen Kosten diese produziert werden könnten, diskutieren wir mit Thorsten Herdan, Europa-Geschäftsführer von HIF. Sonne und Wind werden für die Stromerzeugung immer wichtiger. Doch erneuerbare Energieträger deckten im vergangenen Jahr nur etwa 20 Prozent des gesamten Energiebedarfs in Deutschland. 36 Prozent hingegen entfielen auf importiertes Mineralöl, das vor allem im Verkehr genutzt wird. Einen Ersatz für diese Energiemenge hierzulande klima- und umweltfreundlich zu erzeugen, ist eine Mammutaufgabe. Doch ist das überhaupt notwendig? Wäre es nicht möglich, Strom auch in schwach besiedelten Weltregionen erzeugen und dann als E-Fuels – also als synthetische Kraftstoffe – nach Deutschland transportieren? Oder ist das eine allzu schlichte Idee, weil auf diesem Weg viel zu viel Verluste entstehen? Diese Frage diskutieren wir mit Thorsten Herdan, Europa-Geschäftsführer von HIF, dem Unternehmen, das im Süden Chiles auf einer Pilotanlage schon synthetischen Kraftstoff für Porsche produziert. Als diplomierter Maschinenbauer steckt Herdan einerseits tief in der Technik, aufgrund seiner Karriere, die ihn zwischenzeitlich unter anderem ins Bundeswirtschaftsministerium führte, kennt er aber auch die energiepolitischen Zusammenhänge genau. E-Fuels sieht Herdan nicht als Konkurrenz zu einer Elektrifizierung des Straßenverkehrs, sondern als ergänzende Technologie, die für große Teile der Luft- und der Schifffahrt ohnehin notwendig wird. Technisch sei die Machbarkeit nachgewiesen, allein die Abscheidung des Kohlendioxids aus der Luft noch eine Herausforderung. Langfristig wäre auch eine wirtschaftliche Produktion mit Herstellkosten von 1,50 Euro je Liter synthetisches Benzin möglich. Eine Kostenparität zu fossilem Kraftstoff scheint allerdings nicht in Sicht, deshalb fordert Herdan politische Unterstützung, beispielsweise durch Einführung fester Quoten, wie sie für in Europa genutzte Flugtreibstoffe bereits vorgesehen sind.

This week on HIF player we embark on a classical music journey with musician and writer Oliver Condy recorded live at Berwins Salon North. Using his years of experience to prescribe remedies for all manner of ailments in the form of classical music and offer musical prescriptions that offer comfort, solace and strength in the face of dark times.

Cleaner alternatives to the oil and gas that power vital industries are necessary for economy-wide decarbonization. E-fuels, or electrofuels, are touted as a carbon neutral solution for the hard-to-decarbonize sectors that rely on energy dense fossil fuels.  E-fuels are made by combining hydrogen with carbon dioxide. Through the electrolysis process, water is split into oxygen and hydrogen atoms. The hydrogen is then combined with CO2 through a process called synthesis. The outcome is an energy-dense liquid, synthetic fuel.  But currently, the e-fuels production process makes these alternatives more expensive than fossil fuels. And when burned, they release CO2, making critics question the claims of climate neutrality.  So, what is the climate impact of e-fuels? What industries are turning to these alternatives for decarbonization? And how can policy and tax incentives make them cost competitive with conventional oil and gas?  This week host Bill Loveless talks with Meg Gentle about the use of e-fuels for transport.  Meg is the executive director of HIF Global, an e-fuel company developing some of the largest projects around the world. Before joining HIF, Meg served as the director of Ovintiv, an independent petroleum company, and as the president and CEO of the natural gas company Tellurian. She also spent ten years working for Cheniere Energy, helping grow their LNG marketing and trading company into a world-wide business.  

I helgen vann Arsenal en ny titel och svenske tränaren Jonas Eidevall fick se Stina Blackstenius avgöra i förlängning mot Chelsea. Efter matchen hamnade Eidevall i rubrikerna efter att Chelseas tränare Emma Hayes knuffat honom och talat om manlig aggression. När jag poddintervjuade Eidevall i juni 2023 talade han om drömjobbet att leda Arsenal, om hur ledningen ser möjligheter genom att satsa än mer på damerna, om att ordna klubbens första titel på flera år, om det skulle bli fler svenskor i Arsenal, om att spela fler matcher på Emirates, om de många allvarliga skadorna i klubben och om hur mycket samröre han har med Mikel Arteta. Dessutom berättade Jonas Eidevall om vägen fram som fotbollstränare, om att skifta mellan herr- och damklubbar, om när han vågade släppa bankjobbet, om när han fick förvarna MFF-polarna om HIF-jobbet, om de herrallsvenska bud han nobbat och om att bli förbundskapten i framtiden. Hosted on Acast. See acast.com/privacy for more information.

I 1. halvleg af Fodbold FM lægger vi SL-grundspillet ned for denne gang, hvor vores gæster fremhæver de største skuffelser og positive historier fra sæsonen og ser frem mod et hæsblæsende mesterskabs- og nedrykningsspil. Derudover begynder vi enkeltvis gennemgangen af klubbernes præstationer.Afsnittet forløber således:00:00 - 15:50 - Præsentation af gæster, skulderklap og tacklinger15:50 - 34:42 - Tendenser, skuffelser og overraskelser fra grundspillet 23/2434:42 - 54:25 - Gennemgang af klubbernes grundspil: HIF, VBK, RFC & VFFPanelet består af manden bag Campo.dk, Allan Hvid, sportsjournalist på BOLD, Daniel Nøjsen Fallah, og tidligere branding- og kommunikationsdirektør i Arbejdernes Landsbank, Peter Froulund.Udsendelsens vært er Sebastian Peebles, mens Kasper Damgaard Kristensen agerer producer og tilrettelægger. See omnystudio.com/listener for privacy information.

Esta semana Uruguay dio un nuevo paso para ubicarse como un país productor de combustibles sintéticos, un energético que va ganando terreno a medida que avanza la agenda contra el calentamiento global. El miércoles pasado el gobierno firmó un memorando de entendimiento con la multinacional HIF, que prevé construir en Paysandú una planta de producción de e-fuels, que incluye una gran usina generadora de hidrógeno verde. De concretarse, sería la mayor inversión privada en la historia del país, cercana a los 6.000 millones de dólares, y crear unos 3.000 empleos durante la construcción. Ahora deberá estudiarse la factibilidad del proyecto para después llegar al contrato de inversión. Pero además de esta iniciativa, hay otras que buscan instalarse en Uruguay para producir combustibles limpios. Si se confirman se generará toda una nueva economía vinculada a estos productos, lo que impone desafíos en lo regulatorio, la logística y el monitoreo ambiental. Con el objetivo de abordar estos temas desde fines del año pasado existe la Asociación Uruguaya del Hidrógeno, que reúne a varias cámaras empresariales, relacionadas con este rubro. Vamos a internarnos un poco más en esta nueva economía del hidrógeno verde, sus ventajas y sus exigencias. Conversamos En Perspectiva con Fernando Schaich, ingeniero Químico, socio Fundador de SEG Ingeniería y miembro del directorio de la la Asociación Uruguaya del Hidrógeno.

STARFIGHTER DAN X2M.166 QWAKE הַנְחַת hǎ·neḥǎṯʹ pull back; travel down; penetrate; flatten, sink; deport verb, Hifʿîl, imperative, second person, masculine, singular ± active WAIT-DELIVERANCE PROTOCOL ”May Dan be a snake beside the road, a viper by the path, that bites the heels of the horse so that its rider falls backward. I wait for your deliverance, O Lord.“ ‭‭Genesis‬ ‭49‬:‭17‬-‭18‬ ‭NET‬‬ THE DESCENT OF STARFIGHTER ”Let the weak say, ‘I too am a warrior!' Hasten and come, all you surrounding nations, and gather yourselves to that place.” Descend, Yahweh, your champions!“ Joel‬ ‭3‬:‭10‬-‭11‬ ‭ FROM THE STATE OF DUST/REST X2M.164 QUIESCENCE TO QWAKE/AWAKENING THE X2M.165 QUASIMODOGENITI ”Will it go down to the barred gates of death? Will we descend together into the dust?”“ Job‬ ‭17‬:‭16‬ ‭NET‬‬ DESCENT TO ASCENT: OUT OF EXILE ”Therefore it says, “When he ascended on high he captured captives; he gave gifts to men.” Now what is the meaning of “he ascended,” except that he also descended to the lower regions, namely, the earth? He, the very one who descended, is also the one who ascended above all the heavens, in order to fill all things.“ ‭‭Ephesians‬ ‭4‬:‭8‬-‭10‬ ‭NET‬‬ EXIT TO MILLENNIUM ”For the Lord himself will come down from heaven with a shout of command, with the voice of the archangel, and with the trumpet of God, and the dead in Christ will rise first. Then we who are alive, who are left, will be suddenly caught up together with them in the clouds to meet the Lord in the air. And so we will always be with the Lord.” ‭‭1 Thessalonians‬ ‭4‬:‭16‬-‭17‬ ‭NET‬‬ Glorification | The Final Frontier Going Boldly Where The Last Man has Gone Before! Decrease time over target:  PayPal or Venmo @clastronaut Cash App $clastronaut

You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, members of the Cancer.Net Editorial Board discuss the latest research, innovations, and discussions taking place across the field of genitourinary cancers, including prostate cancer, bladder cancer, kidney cancer, and testicular cancer. This podcast is led by Cancer.Net Associate Editor for Genitourinary Cancers, Dr. Petros Grivas. Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine and a professor in the clinical research division at the Fred Hutchinson Cancer Research Center. He is joined by Dr. Neeraj Agarwal, Dr. Shilpa Gupta, Dr. Tian Zhang, and Dr. Timothy Gilligan. Dr. Agarwal is a Professor of Medicine, and a Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah. He directs the Genitourinary Oncology Program and Center of Investigational Therapeutics at the Huntsman Cancer Institute. He is also the Cancer.Net Specialty Editor for Prostate Cancer. Dr. Gupta is the Director of the Genitourinary Medical Oncology Program at Taussig Cancer Institute and Co-Leader of the Genitourinary Oncology Program at Cleveland Clinic. She is also the Cancer.Net Specialty Editor for Bladder Cancer. Dr. Zhang is an Associate Professor of Internal Medicine at UT Southwestern Medical Center and a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center. She is also the Cancer.Net Specialty Editor for Kidney Cancer. Dr. Gilligan is a Medical Oncologist, Associate Professor of Medicine, and Vice-Chair for Education at the Cleveland Clinic Taussig Cancer Institute. He is also the Cancer.Net Specialty Editor for Testicular Cancer.  View full disclosures for Dr. Grivas, Dr. Agarwal, Dr. Gupta, Dr. Zhang, and Dr. Gilligan at Cancer.Net. Dr. Grivas: Hello. I'm Dr. Petros Grivas. I'm a medical oncologist in Seattle, a professor at the University of Washington and Fred Hutchinson Cancer Center. I'm really excited and thrilled today to host wonderful superstars in the field of GU Medical Oncology who will share insights about the highlights of kidney cancer, prostate cancer, and bladder, urothelial, urinary tract cancers that happened in 2023. And this highlight aims to inform our great audience about what are the clinically relevant insights, what patients should be aware, what patients should ask for when they go to the clinic, or overall, how they can be most well-informed and have the necessary tools to improve their care and feel well-supported in regards to education. So without further ado, we're going to cover in first prostate cancer, a very important update in this year. So all the people out there that are interested in hearing about prostate cancer will find this very, very useful and insightful. I'm very excited to host Professor, Dr. Neeraj Agarwal from University of Utah. Neeraj, do you want to introduce yourself? Dr. Agarwal: Of course. It's such an honor to be here. My name is Dr. Neeraj Agarwal. I'm a professor of medicine and director of genitourinary oncology program at the University of Utah Huntsman Cancer Institute. Dr. Grivas: Neeraj, thank you so much for accepting the invitation and being with us. I would like to ask you, what's your take on the current state of genetic testing in patients with prostate cancer? And when we say genetic testing, maybe you can clarify the distinction between germline and somatic and comment on both if you could. Thank you. Dr. Agarwal: Of course, a very important topic. I must tell you that it is very clear from all the guidelines that in patients with advanced prostate cancer or metastatic prostate cancer, meaning when prostate cancer has spread to different parts of the body, both germline testing to look for hereditary mutations in the DNA repair genes and testing for the same genes inside the tumor tissue are considered standard of care. So, a patient with advanced prostate cancer should have germline testing and somatic tumor tissue testing to look for mutations that can predispose them to have prostate cancer, and if they have genes in the tumor which can be targeted by the current approved drugs, like drugs which are already approved right now or which are in clinical trials. Unfortunately, less than 50% of patients in many areas of the country and in the world, less than 20% of patients are being tested. And even more, unfortunately, patients are less likely to be tested are those who are not well-resourced, who are not living in rich countries, if you will. They are poor- or low-resourced countries. Even with high-income countries, within those countries, patients who are living in relatively not-so-affluent neighborhoods, they are less likely to be tested. From racial perspective, patients who are Black or who are Hispanics are less likely to be tested. Based on how many drugs are out there in the clinic and emerging through clinical trials. And the fact that we can use many of these mutations for prognostication, to inform survival, to inform aggressiveness of the disease. It is not only to treat those patients, but also how to monitor the disease. The genetic testing is very important. Dr. Grivas: Thank you so much, Neeraj. It's very insightful. And I think you did a great job outlining the clinical relevance for both the patient in terms of treatment decision-making and therapy options, especially for advanced prostate cancer, as well as the broader family and implications for cancer prevention and cancer screening for the broader family members. So definitely a very important topic. Neeraj, the other question I have, if you could tell us more about this class of medications called PARP inhibitors. If you can comment on the currently approved PARP inhibitors, either as a single agent, what we call monotherapy or combination therapies for patients with prostate cancer in the United States, and who is eligible to receive those therapies? Dr. Agarwal: And this is such a nice segue to talk about PARP inhibitors as we were just talking about genetic testing of prostate cancer. So, PARP inhibitors are a class of drug which are instrumental, critical in treatment of patients who harbor mutations in those DNA repair genes. And two monotherapies, meaning using these PARP inhibitors as single agents have been already approved in the United States and several other countries. These are olaparib or rucaparib. Olaparib is approved after patients have had disease progression on novel androgen-blocking therapies or androgen blockers such as enzalutamide or abiraterone or apalutamide. And these PARP inhibitors such as olaparib or rucaparib can be used for those patients as single agent if they have these DNA repair mutations. Now, last year, we saw several combinations of PARP inhibitors with these androgen or novel hormonal therapy, as we call them. And these include abiraterone plus olaparib, abiraterone plus niraparib, and talazoparib plus enzalutamide from various phase 3 trials. Now, I'd like to bring to your attention that these PARP inhibitor combinations are approved with different indications in the United States and in the European Union. And they continue to get approved in various other countries. So the combination of abiraterone and a PARP inhibitor, whether it is olaparib or niraparib, they are approved for patients who have new metastatic castrate-resistant prostate cancer, and they have BRCA1 or BRCA2 mutations in the cancer cells or they have germline BRCA1 and BRCA2 mutations. Enzalutamide and talazoparib combination is approved in the United States for patients with metastatic castration-resistant prostate cancer with BRCA1 and BRCA2 mutations, but also several other DNA repair gene mutations. And that's a big difference as far as approval is concerned in the U.S. In the European Union, for our patients who are listening from European Union, the combination of abiraterone and olaparib and enzalutamide and talazoparib are approved for patients with metastatic castrate-resistant prostate cancer where chemotherapy is not clinically indicated, regardless of whether they have mutations in the DNA repair genes or not. And the combination of abiraterone and niraparib is only approved for patients with metastatic castrate-resistant prostate cancer with BRCA1 and BRCA2 mutation. So I just wanted to outline the different indications in the United States and in the Europe. Dr. Grivas: Thank you so much, Neeraj. So eloquent and very relevant to multiple patients globally, as you pointed out, with some differences in terms of the regulatory approval and availability of those agents in different countries. So great insights. Maybe we'll ask you 1 more question again since we are doing the highlights of the year. Another very important area of therapeutic development has to do with these novel agents that target the prostate cancer cells, and we call them theragnostics as a broader term. And I will let you explain what that means maybe in lay terms for our audience. And specifically, if you can comment on the recently presented PSMAforetrial at the ESMO meeting in Madrid with lutetium-177 PSMA. What are the implications of these results for our patients, and what is the role of lutetium therapy in this particular therapy setting? Dr. Agarwal: Of course, very important and pertinent topic indeed. As our patients may know that lutetium-177 therapy, or simply speaking, lutetium therapy, has already been approved for patients with metastatic castrate-resistant prostate cancer who have had disease progression on this novel hormonal therapy and a chemotherapy with docetaxel or cabazitaxel. And this indication is already there in the U.S. and in various other countries. And patients are eligible to receive lutetium therapy as long as their disease has progressed on docetaxel or one of the taxane chemotherapy and a novel hormonal therapy. Now, in the European Society of Medical Oncology meeting, Dr. Oliver Sartor presented the data on PSMAfore trial where lutetium therapy was used before chemotherapy. In this trial lutetium therapy was compared with another novel hormonal therapy after disease progression on 1 novel hormonal therapy. And there was approximately 6-month improvement in progression-free survival, meaning there was a delay in disease progression by 5 to 6 months in patients who were receiving lutetium therapy. And at the time of the report, there was no improvement in overall survival, with the caveat that 84% patients who were receiving novel hormonal therapy, actually, they switched over to lutetium therapy after disease progression. So, overall, survival data may not be met. Having said that, we already know that lutetium therapy is an effective therapy, and it has a definitive role in treatment of our patients with metastatic castrate-resistant prostate cancer. Dr. Grivas: Thank you, Neeraj. That's very, very important data. And I'm so glad we have many more therapy options for our patients with prostate cancer. So involvement and accrual in clinical trials, I'm sure you will agree, is a very important and high priority. And I always encourage people with prostate cancer to ask about clinical trials that are relevant to their situation. Dr. Agarwal: Yeah. I'd just like to add a point regarding lutetium therapy that there was a phase 2 trial in from Australia which compared lutetium therapy with cabazitaxel therapy after disease progression and docetaxel chemotherapy. And efficacy of both agents were not very different. So just wanted to make that point. Dr. Grivas: Thank you, Neeraj. It's a very important point. And obviously, always want to think about pace and preference, convenience, distance from the cancer centers, all the relevant points, how we can individualize suggestions or recommendations for our patients. Thank you so much, Neeraj, for your wonderful input, insights, and all the work you do in the field. Dr. Agarwal: Thank you very much for having me. Dr. Grivas: Of course, of course. And now we're going to transition to a different cancer type. We're going to talk about bladder cancer and urothelial cancer in general, urinary tract cancer. And we're delighted and excited to have Dr. Shilpa Gupta from Cleveland Clinic, who's a professor there of oncology. Shilpa, I want to introduce yourself? Dr. Gupta: I'm Shilpa Gupta. I'm a genitourinary medical oncologist and the director of the GU Program at Cleveland Clinic. I'm really excited to be doing this podcast with you all. Dr. Grivas: Thank you, Shilpa. You have done amazing work in the field, pushing the field forward. You are part of those transformative studies. I will ask you in the beginning where I'm going to focus my first question for people who have advanced or metastatic bladder cancer or urinary tract cancer or upper or lower tract. And we saw really exciting, impressive data at the recent ESMO Congress in Madrid a couple of months ago. And I know you were there and were enjoying to see the improvement in patient outcomes that comes with better quality of life for patients in the last several years. And the question I have for you, if you want to summarize the key data in the first-line treatment, patients who have no prior treatment for metastatic urothelial cancer, what are the key data we showed at the ESMO meeting? Dr. Gupta: Thank you, Petros. As you said, this is a really exciting time for both patients as well as the physicians treating bladder cancer because of all the new developments which we've seen after decades. So at ESMO 2023, we saw the key data from the EV-302 trial, which was a phase 3 trial, which randomized patients to the standard of care, platinum-based chemotherapy, gemcitabine-cisplatin or gemcitabine-carboplatin, versus a novel drug, which is an antibody-drug conjugate called enfortumab vedotin and the immunotherapy pembrolizumab. And the primary endpoint was to see if patients lived longer and this delayed progression. And we saw that in this the progression-free survival, we saw that it was 12.5 months with enfortumab vedotin and pembrolizumab compared to 6.3 months, which means that the risk of progression or death was decreased by 55% with this new combination. And the benefit was seen across all the various factors, especially patients with liver metastases, visceral metastases, whether or not they had contraindications to receiving cisplatin or not or PD-L1 expression. So this is the first time we saw such a remarkable benefit with any treatment that beat platinums. And the overall survival was also doubled: 16 months in chemotherapy versus 31.5 months with this combination. So the risk of death was reduced by 53%. And we also saw that the overall response rates were 68% with this compared to 44% with chemo. And 29% of patients had complete responses. And this was really remarkable because we have not seen such data before. And in the same session, we also saw another phase 3 trial that was presented, which was the Checkmate 901 trial, in which the investigators tested whether the addition of immunotherapy called nivolumab to the standard of care, gemcitabine and cisplatin was better than gemcitabine and cisplatin alone. So this was a study only looking for patients who can receive cisplatin. So patients were randomized to 6 cycles of gemcitabine cisplatin versus nivolumab, gemcitabine cisplatin for up to 6 cycles. And after that, they continued nivolumab maintenance every month for up to 2 years. And in this, the primary endpoint of overall survival was also met, although the difference was not as huge as the other study. It was 18.9 months with chemotherapy versus 21.7 months with the combination. And progression-free survival was also improved by just 0.3 months with the combination. And the objective response rates were higher with the combination, 57% versus 43%, and there were 21% complete responses. So the bottom line is that both these trials showed us that the frontline treatment is not going to be just platinums anymore moving forward. We will have the option of the enfortumab vedotin and pembrolizumab for all comers, patients who can get platinums, and nivolumab and gemcitabine cisplatin for patients who are cisplatin eligible. Dr. Grivas: Thank you, Shilpa. Wonderful summary. Really, really exciting time to see the field moving forward and translate those results to longer life for our patients. In that context, I will also ask you—I asked Neeraj before about genetic testing in prostate cancer. I will ask you a similar question about genetic testing in bladder cancer. Again, reminding the audience about the distinction between germline testing, which is the DNA we are born with, and somatic testing, which is the cancer-specific genomic changes. Could you comment on the importance of genetic testing in bladder cancer? Dr. Gupta: Yes. Absolutely, Petros. Genetic testing in urothelial cancer is very important because for the first time a few years ago, we saw a drug targeting the fibroblastic growth factor receptor or FGFR alterations. This drug is called erdafitinib. It is the first targeted therapy to be approved in urothelial cancer. It is only seen in up to 20% of patients who harbor these alterations for whom this option may be viable. And we saw initially that erdafitinib was approved in patients who harbor these alterations in the phase 2 BLC2001 trial where it showed response rates of 40% and encouraging progression-free survival, and overall survival. And then we also saw in a phase 3 trial called the THOR trial where patients who harbored these alterations by genetic testing, erdafitinib was much better than chemotherapy, prolonged survival by almost 4.2 months compared to chemotherapy. So unless we are testing, we won't find this. So it is really important to test all our advanced disease patients so we are not depriving them of this additional targeted therapy. Dr. Grivas: Thank you, Shilpa. Very important message for our patients to definitely discuss the value of genetic testing. And if we think about therapy implications, specifically genomic changes, DNA changes in these FGFR-2 and FGFR-3 genes are very relevant and important for potential therapy with this agent called erdafitinib. Shilpa, a quick comment. We saw data from THOR cohort 2 comparing erdafitinib with this inhibitor of this FGFR that we just talked about compared to pembrolizumab, which is an immunotherapy drug inhibiting a checkpoint of the immune system. Could you quickly comment on that? And I think both options are available for our patients and sometimes just comes down to the sequence based on a particular patient case. Dr. Gupta: So Petros, as we had thought that patients who harbor these alterations in their tumors, they may benefit from using targeted therapy before immunotherapy. That was the premise of the cohort 2 of the THOR trial, that patients will do better if they received erdafitinib first after progressing on 1 prior line of therapy, which is not an immunotherapy. So patients were randomized to erdafitinib versus pembrolizumab. Of course, all of them had to have the FGFR alterations. The primary endpoint was overall survival. Initially, like I said, the study assumed that there'll be 46% improvement in overall survival with erdafitinib over pembrolizumab. However, the study was a negative study. There was no difference in the overall survival. And what that means for our patients is that erdafitinib right now is positioned for patients who've had prior platinums and immunotherapies. So erdafitinib should not be used before immunotherapy. So I think this is the first study that really settles the question of sequencing for our patients. And I think the message is that in a patient's journey, they should be getting all these therapies. We just now know that it's better to use pembrolizumab before erdafitinib and not vice versa. Dr. Grivas: Thanks, Shilpa. And then really, really interesting to see these trials being reported. And as you said, individual discussion with the patients and the response rate may be another factor to consider. If someone wants to have a more rapid control of the cancer of the disease, we may potentially think about an agent with high response rate and vice versa. So I think to your point, individual decisions. And I think patients asking those questions is very important in the clinic to help select the right patient for the right treatment for the right patient. Dr. Gupta: Yeah. Absolutely, Petros. They did see that the response rates were 40% with the erdafitinib versus 21% with the immunotherapy. So using that information can sometimes guide us if a patient has high disease burden. Dr. Grivas: Thank you, Shilpa. That was very insightful. And thank you for all you are doing for the patients and the field in general. You really, really have helped the field move forward. So congratulations and thank you. And we're going to transition to another superstar in the field of GU cancers. Very excited to host Dr. Tian Zhang. Dr. Zhang is in UT Southwestern in Dallas. Tian, you want to introduce yourself? Dr. Zhang: Hi, Petros. Thank you so much. Tian Zhang, I'm a GU medical oncologist and associate professor at UT Southwestern Medical Center in Dallas. Dr. Grivas: Wonderful. Thanks, Tian. Again, the same comments. All the work you're doing in the field is tremendous. Thanks for joining us today. Tian, we saw some very interesting data at the ESMO meeting. And since we're doing the highlights of the year, I think the predominance of the data we saw at the ESMO meeting was about this drug called belzutifan, where I will ask you to enlighten us what exactly this is. And particularly, we saw 3 different trials. I would probably ask you to focus more on the LITESPARK-005. What was the trial design and what was the primary goal of the study? When patients go on this drug, what they should be aware in terms of side effects? And what was all this discussion that the take-home message at the end of ESMO regarding belzutifan? Thank you. Dr. Zhang: Sure. We'll parse that one at a time. Belzutifan, I hope many of our audience knows is a small molecule inhibitor of the HIF complex, a hypoxia-inducible factor complex, which is implicated in the development of kidney cancers. And this biology actually contributed to the Nobel Prize in 2019. Understanding the structure of the HIF complex and how to target it. For a long time, HIF was thought to be un-targetable. And so the fact that there were small molecules identified actually here in Dallas at UT Southwestern that inhibits the dimerization of the HIF complex is really novel and shows us the bench-to-bedside translatability of these preclinical discoveries. And so there were a couple of molecules that were discovered here on campus and they paved the way for what became molecules that have now made it to clinic, in particular belzutifan. And so we've had belzutifan now approved for Von Hippel-Lindau Syndrome over the last 2 years or so. So many of us are familiar with using this drug in the clinic. It's an oral agent that's able to target the HIF complex and block it and really control the spread of clear cell kidney cancers, in particular in Von Hippel-Lindau disease.  LITESPARK-005, the trial that you're alluding to, there was a registrational trial for belzutifan across other kidney cancer populations. And this trial was the 1 that made, I think, the biggest impact of the 3 trials that were presented at ESMO this year.  LITESPARK-005 was a phase 3 trial of patients who had metastatic or locally advanced clear cell kidney cancer who had progressed after prior systemic therapies, not more than 3 prior lines. And they were randomized to either belzutifan at the 120 milligrams daily dose or everolimus at the 10 milligrams daily dose. And the primary endpoint was delay of progression. So progression-free survival as well as overall survival. So we saw the primary endpoint of these was met for progression-free survival. There was about a 26% risk reduction for progression for patients treated with belzutifan versus those that were treated with everolimus. The objective response rate I would highlight is also significant for the patients treated with belzutifan. There was actually a 3.5% complete response rate and objective responses. So including partial responders was about 23%. I would say that patients who are treated with belzutifan need to be aware of the side effects of anemia and also hypoxia [low levels of oxygen in the body]. And in fact, higher grades of anemia can occur in up to a third of patients and higher rates of hypoxia. So low oxygen saturations can occur in up to 10% or so of patients. And so that's really important when we're thinking about those toxicities and how we might hold or support the side effects with growth factors, for example, for the anemia. Otherwise, it's quite well tolerated as a single agent. As you alluded to, there was 1 controversial aspect of this particular trial because the control cohort was treated with everolimus. And everolimus as a single agent may not be what people use at this point in the refractory setting. But it is an acceptable approved treatment option for patients in the refractory kidney cancer setting, and therefore, it was chosen as the control cohort. And belzutifan did improve compared to a known standard of treatment. So I think that's really important to add to our armamentarium in refractory disease. Dr. Grivas: Wonderful, Tian. Thank you so much for a really, really comprehensive and detailed review. We'll have to see whether it will be available for patients with advanced clear-cell kidney cancer. To your point, it's already available for patients with this condition that you mentioned, the Von Hippel-Lindau genetic condition. So it's great to see more options available for our patients. Maybe I'll ask you another quick trial to comment on Tian, and I'll ask you individual questions to make it easier, to your point, for the audience to follow. And I'm referring to the RENOTORCH trial. This was conducted in China, and I think it was practice-changing there. Could you tell us the study design? Dr. Zhang: RENOTORCH was another phase 3 randomized trial. It was conducted all in China of patients with unresectable metastatic clear cell kidney cancer, no systemic prior therapy, and also intermediate- and poor-risk disease by IMDC criteria. So these were all first-line metastatic disease, and patients were randomized to either toripalimab, which is their PD-1 inhibitor, plus axitinib versus sunitinib. So this is a trial design that mirrors many of our prior trials in the first-line metastatic setting that have led to approvals of VEGF IO [immunotherapy] combinations. But this is the first one that was carried out purely in the Chinese population and important for the Chinese population to gain access to these types of combinations. Dr. Grivas: Thank you, Tian. Very important to see this global approach, as you mentioned, oncology and see trials from different countries. What were the main findings of this trial? Dr. Zhang: Sure. The primary endpoint was progression-free survival of the 2 cohorts. And they randomized about 420 patients. About 80% per cohort had intermediate-risk disease. And the combination of axitinib with toripalimab did improve progression-free survival. So it had a 35% risk reduction for progression over time. So it did meet its primary endpoint. Dr. Grivas: Thank you, Tian. It's great to see progress in the field. As I mentioned, new agents, positive trials. Could you comment a little bit on the side effect profile and the significance of this trial for our patients worldwide? Dr. Zhang: Sure. When we're talking about VEGF IO combinations very similarly as to the prior trials that we've seen in the toxicity profiles, we're thinking a lot about the immunotherapy toxicities of rashes and colitis [inflammation of the colon], endocrinopathies [hormone problems], as well as the rare inflammatory reactions of the liver, lungs, or kidney, but also added in the small molecule effects of hypertension, hand-foot syndrome, and mucositis [mouth sores] and taste changes. So very important to think through those side effect profiles as our patients are being treated with these combinations. Dr. Grivas: Thank you so much, Tian. Great to see, again, this progress made worldwide. And I think it speaks to the idea of how we can have equitable healthcare delivery across the globe, right, and have agents accessible in different parts of the world. Dr. Zhang: Absolutely. In fact, I would just add that the Chinese population haven't actually had access to drugs like cabozantinib. And this is their first phase 3 grade 1 evidence for a combination of VEGF with IO combination. So it's really important that these trials are carried out in the populations where we try to find the effect and see that the consistent benefit is there so that those patients have access to all of these treatment options. Dr. Grivas: Thank you, Tian. I appreciate your wonderful insights and all your amazing contributions in the field and your research. It's really, really inspiring to see. And I'm going to transition now. Last but not least, we're having the honor of hosting professor, Dr. Tim Gilligan, who is in Cleveland Clinic, and Tim is a world-known expert in urinary cancers, including testicular cancer. Tim, would you like to introduce yourself? Dr. Gilligan: Yes. Hi. So I think you just did. Tim Gilligan, an oncologist at Cleveland Clinic. I chaired the NCCN panel on testis cancer and edit the UpToDate sections on testis cancer with their help. Dr. Grivas: Fantastic. Thanks, Tim, for being with us today. And all the work you have done for our patients with GU cancers, testicular cancer, and a lot of work is being done with the NCCN and other guidelines. And you are co-chairing the NCCN guidelines, to your point. Tim, a lot of discussion is happening nowadays across cancer types regarding the role of what we call biomarkers, which are potential features that can help us select patients for the right treatment or help us estimate the prognosis, how long people live. Could you comment a little bit on this biomarker called microRNA in patients with testis cancer? How do you envision this being developed in the future? Is it ready for prime time or not yet? Dr. Gilligan: And that's an important question. It's not ready for prime time yet, but we are making progress. There are a couple of areas where it could be very useful. So for example, in stage I testicular cancer, we tell patients to go on surveillance because they're usually cured with orchiectomy [surgical removal of the tumor and testicle], but there is a risk of relapse, and that risk of relapse is highly variable. And our current risk stratification systems for predicting who's going to relapse, who has stage 1 disease, are helpful, but they're far from perfect. And so there was data presented this year that mRNA may be more accurate at predicting for men with stage I non-seminomas who's destined to relapse. And so the implication of that would be if you are positive for mRNA, this particular mRNA for non-seminoma and you have stage I disease, normal scans, normal markers, you could identify a high-risk group of patients who maybe should get a cycle of BEP chemotherapy rather than waiting. If you know they're going to relapse, you're going to have to get them 3 cycles of BEP, why not just treat them right away? Or maybe RPLND [retroperitoneal lymph node dissection] could be helpful in that setting. We don't know. But we would need to do studies validating that approach. There is data showing that it does predict relapse, but it's not at the point of saying, "Are the patients really going to do better with immediate treatment and which treatment is going to be best for them?" But I thought that was an important finding and really an example of how we think we're going to use it, which is to find relapse a lot earlier and so that we can give a less toxic treatment. And the benefit of that is that we know more and more that chemotherapy is toxic and resulted in second cancers. For men who get multiple cycles of cisplatin-based chemotherapy, or if they get radiation therapy, they're at higher risk of dying of other cancers than the general population. So if this could help us find early relapses, treat it more gently, less aggressively, have late, less toxicity, and the same cure rate. That would be great. So we're not there yet, but I think we're going to get there. Dr. Grivas: Thanks, Tim. Very, very helpful to know. So this microRNA 371 that we talk about is not ready for prime time, but you definitely see promise for the future, and more trials, more studies are being done. Again, illustrating the importance of clinical trials that can help us evaluate the added value of a particular biomarker, including this particular microRNA that we talked about. Dr. Gilligan: Before you change the subject on getting to crude biomarkers, there was also an interesting abstract showing that for stage I seminoma. If we actually use our current markers, we may be able to predict much more accurately. And it'll be interesting to see if that changes. They looked at the variables of lymphovascular invasion, invasion of the hilum of the testis, whether or not preoperative markers were elevated, LDH, and beta HCG. What was interesting to me about that paper was that this is about 900 patients. It was pretty large. That if you had all 4 risk factors, the relapse rate was about 64%. Whereas your average relapse risk for stage I seminoma is about 15%. We put everyone on surveillance. If we started if that model is persuasive to the community and starts getting used, then maybe patients with those 4 risk markers who most of whom are going to relapse, according to this data, maybe you want to treat those people and not put them on surveillance. So that'll be interesting to follow up on too. Dr. Grivas: Thanks, Tim. And you are referring to currently available blood tests, right, that can be used, and we use them in clinical practice. So we just put them together, try to get a sense of the chance of cancer coming back, what we call recurrence, and how long people may live. That can help us make a therapy decision. Thank you, Tim. This is very, very interesting. And I'm glad to see the progress in the field. I think you alluded to that before, but there is a trend discussing when we have a removal of the testicle for a patient with testis cancer, what to do next, depending on the stage, those markers that the blood tests you told us about. What about the role of surgery for removal of lymph nodes, for example? And do you see a trend going forward that in many selective cases, certain scenarios, we may potentially select surgery as opposed to chemotherapy or radiation to avoid these potential complications down the road? And if so, which are those patients who may benefit from surgery? Dr. Gilligan: Yeah, an important question. I think surgery, there's been a growing interest in using surgery rather than chemotherapy in order to avoid late effects. So retroperitoneal lymph node dissection (RPLND) is the most obvious example of that. There is data now showing that most patients with stage II seminoma can be cured with retroperitoneal lymph node dissection. We used to treat those patients with chemotherapy or radiation, but as I've noted, both of those are associated with an increased risk of second cancers down the line. So there are papers on both sides of the Atlantic showing that you can cure most people. However, it is important to note that the relapse rate after surgery is significantly higher than the relapse rate after chemotherapy or radiation. If you take a stage II patient and treat them with chemotherapy or radiation, you're going to cure well over 90% of them. Whereas the relapse risk with surgery, depending on what you find at surgery, is going to be higher. So on average, it's going to be in the realm of 20%, maybe as high as 30%, depending on which paper you look at. And if you take patients who have PN2 disease, so a lymph node is 2 centimeters or bigger, 25% or more of those patients are relapsing after surgery. So it's important for patients to understand that this treatment has the benefit of avoiding chemotherapy for most patients, but it also has a higher risk of relapse than the old treatments. We still think it's attractive because if you can avoid chemotherapy in 3 out of 4 patients or 4 out of 5 patients, that's a benefit to those patients. And also, if you go in and find a significant amount of cancer at surgery, you can give 2 cycles of chemotherapy right away and almost eliminate the risk of relapse, which is less chemo than they would be getting upfront, which would be 3 or 4 cycles. So one of the emphasis now is really trying to avoid late toxicities if we can. You sometimes see that even in the metastatic setting in terms of resecting residual masses and situations where we maybe in the past would have thought about second-line chemotherapy. I think people are more thinking about opportunities to use surgery instead to try to limit the quantity of chemo that we're giving. Those are much trickier decisions than the stage II decisions, but definitely a growing interest in surgery rather than chemo. Dr. Grivas: Thank you so much. It's really, really exciting to see that testis cancer was really transformed in the past with developments of therapies like chemotherapy, radiation therapy, and surgery. And it's great to see this evolving down the road. And I think all of the above that you mentioned evolves through the conduction of clinical trials. And as I mentioned before, I think it's so important to give the opportunity for patients and families to review clinical trial options. I think it's critical to try to help them, but also help other patients, the community, the society in general. So I always try to underline the importance of clinical trials across the board. And on that note, I think we had such a successful year, 2023 across GU cancers. It's so great to see the progress being made. All of us are looking forward for more exciting research being done in 2024 and beyond. And on that note, I want to thank so much Dr. Agarwal, Dr. Gupta, Dr. Zhang, and Dr. Gilligan for wonderful insights and all the great work they're doing in the field of GU cancers. As the editor for the GU Cancers for the wonderful Cancer.Net, I'm so proud of this team and really, really looking forward to further podcasts like this and how we can better serve the educational mission for ASCO, working with the wonderful staff at Cancer.Net. Thank you so much, all of you, for your time today and all you are doing. Dr. Gupta: Thank you, Petros. Dr. Zhang: Thank you, Petros. ASCO: Thank you, Dr. Grivas, Dr. Agarwal, Dr. Gupta, Dr. Zhang, and Dr. Gilligan. You can learn more about new research in genitourinary cancers at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Drs. Neeraj Agarwal and Jeanny Aragon-Ching discuss several key abstracts to be presented at the 2024 ASCO GU Cancers Symposium, including sequencing versus upfront combination therapies for mCRPC in the BRCAAway study, updates on the CheckMate-9ER and CheckMate-214 trials in ccRCC, and a compelling real-world retrospective study in mUC of patients with FGFR2 and FGFR3 mutations. TRANSCRIPT Dr. Neeraj Agarwal: Hello, everyone, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of ASCO Daily News. I am delighted to welcome Dr. Jeanny Aragon-Ching, a genitourinary oncologist and the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters and oral abstracts that will be featured at the 2024 ASCO Genitourinary Cancer Symposium, which is celebrating 20 years of evolution in GU oncology this year.  You will find our full disclosures in the transcript of this podcast, and disclosures of all guests on the podcast at asco.org/DNpod.  Jeanny, it's great to have you on the podcast today to highlight some key abstracts for our listeners ahead of the GU meeting. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. It's an honor to be here. Dr. Neeraj Agarwal: Jeanny, as you know, this year we are celebrating the 20th anniversary of the ASCO GU Cancers Symposium, and judging from this year's abstracts, it's clear that this meeting continues to play a major role in advancing GU cancer research. Dr. Jeanny Aragon-Ching: Indeed, Neeraj. This year's abstracts reflect the important strides we have made in GU cancers. So, let's start with the prostate cancer abstracts. What is your takeaway from Abstract 19 on BRCAAway, which will be presented by Dr. Maha Hussein, and of which you are a co-author? As our listeners know, several PARP inhibitor combinations with second-generation androgen receptor pathway inhibitors, or ARPIs, have recently been approved as first-line treatment for patients with metastatic castrate-resistant prostate cancer, or metastatic CRPC, and the question of sequencing PARP inhibitors and ARPIs instead of combining them has emerged. From that perspective, the results of the BRCAAway trial are very important. Can you tell us a little bit more about this abstract, Neeraj?  Dr. Neeraj Agarwal: I totally agree with you, Jeanny. The BRCAAway study attempts to answer the crucial questions regarding sequencing versus upfront combination of therapies in the mCRPC setting. It is a phase 2 trial of abiraterone versus olaparib versus abiraterone with olaparib in patients with mCRPC harboring homologous recombination repair mutations. Enrolled patients had mCRPC disease and no prior exposure to PARP inhibitors or ARPIs or chemotherapy in the mCRPC setting and had BRCA1 or BRCA2 or ATM mutations. As previously mentioned, these patients were randomized to 3 arms: abiraterone monotherapy at 1000 milligrams once daily, or olaparib monotherapy at 300 milligrams twice daily, or the combination of abiraterone and olaparib. The primary endpoint was progression-free survival per RECIST 1.1 or Prostate Cancer Working Group 3-based criteria or clinical assessment or death, so, whichever occurred first was deemed to be progression.   Secondary endpoints included measurable disease response rates, PSA response rate, and toxicity. This was a relatively small trial with 21 patients in the combination arm, 19 patients in the abiraterone monotherapy arm, and 21 patients in the olaparib monotherapy arm. It should be noted that 26% of patients had received docetaxel chemotherapy in the hormone-sensitive setting, and only 3% of patients had any prior exposure to an ARPI, and these were darolutamide or enzalutamide or in the non-metastatic CRPC setting.  The results are very interesting. The median progression-free survival was 39 months in the combination arm, while it was 8.4 months in the abiraterone arm and 14 months in the olaparib arm. An important finding that I would like to highlight is that crossover was also allowed in the monotherapy arms. Of the 19 patients receiving abiraterone, 8 crossed over to receive olaparib, and of the 21 patients receiving olaparib, 8 crossed over to the abiraterone arm. The median PFS from randomization was 16 months in both groups of patients who received abiraterone followed by olaparib or those who received olaparib followed by abiraterone. This is striking when compared to 39 months in patients who started therapy with the combination therapy of abiraterone with olaparib. Dr. Jeanny Aragon-Ching: Thank you so much for that wonderful summary, Neeraj. So the key message from this abstract is that combining olaparib and abiraterone upfront seems to be associated with improvement in PFS compared to just sequencing those agents. Dr. Neeraj Agarwal: Exactly, Jeanny. I would like to add that these results are even more important given that in real-world practice, only half of the patients with mCRPC receive a second-line treatment. Based on these results, upfront intensification with a combination of an ARPI plus a PARP inhibitor in the first-line mCRPC setting seems to have superior efficacy compared to sequencing of these agents. Dr. Jeanny Aragon-Ching: Thank you so much. Now, moving on to a different setting in prostate cancer, there were a couple of abstracts assessing transperineal biopsy compared to the conventional transrectal biopsy for the detection of prostate cancer. So let's start with Abstract 261. Neeraj, can you tell us a little bit more about this abstract? Dr. Neeraj Agarwal: Sure, Jeanny. So, in Abstract 261 titled "Randomized Trial of Transperineal versus Transrectal Prostate Biopsy to Prevent Infection Complications," Dr. Jim Hugh and colleagues led a multicenter randomized trial comparing these 2 approaches, so, transperineal biopsy without antibiotic prophylaxis with transrectal biopsy with targeted prophylaxis in patients with suspected prostate cancer. The primary outcome was post-biopsy infection. Among the 567 participants included in the intention-to-treat analysis, no infection was reported with the transperineal approach, while 4 were detected with the transrectal approach, with a p-value of 0.059. The rates of other complications, such as urinary retention and significant bleeding, were very low and similar in both groups. The investigators also found that detection of clinically significant cancer was similar between the 2 techniques and concluded that the transperineal approach is more likely to reduce the risk of infection without antibiotic prophylaxis. Dr. Jeanny Aragon-Ching: So the key takeaway from this abstract sounds like office-based transperineal biopsy is well-tolerated and does not compromise cancer detection, along with better antibiotic stewardship and health care cost benefits.  Moving on to Abstract 273, also comparing these two approaches, what would be your key takeaway message, Neeraj?  Dr. Neeraj Agarwal: In this Abstract 273, titled "Difference in High-Risk Prostate Cancer Detection between Transrectal and Transperineal Approaches," Dr. Semko and colleagues found that the transperineal biopsy based on MRI fusion techniques was also characterized by a higher possibility of detecting high-risk prostate cancer and other risk factors as well, such as perineural and lymphovascular invasion or the presence of cribriform pattern, compared to the conventional transrectal method. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So we can see that the transperineal approach is gaining more importance and could be associated with more benefits compared to the conventional methods.   Let's now switch gears to kidney cancer, Neeraj. Dr. Neeraj Agarwal: Sure, Jeanny. Let's start by highlighting Abstract 361, which discusses patient-reported outcomes of the LITESPARK-005 study. So what can you tell us about this abstract, Jeanny?  Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So as a reminder to our listeners, based on the LITESPARK-005 trial, it was a Phase 3 trial looking at belzutifan, which is an inhibitor of hypoxia inducible factor 2 alpha or I'll just call HIF-2 alpha for short, was very recently approved by the FDA as a second-line treatment option for patients with advanced or metastatic clear cell renal cell carcinoma after prior progression on immune checkpoint and antiangiogenic therapies. The title of Abstract 361 is "Belzutifan versus Everolimus in Patients with Previously Treated Advanced RCC: Patient-Reported Outcomes in the Phase 3 LITESPARK-005 Study," and this will be presented by Dr. Tom Pells at the meeting. At a median follow-up of 25.7 months, the median duration of treatment with belzutifan was 7.6 months, while it was only 3.9 months with everolimus. At the time of data cutoff date for the second interim analysis, 22.6% of patients remained on belzutifan while only 5% remained on everolimus. In the quality of life questionnaires, the time of deterioration to various quality of life scores, as assessed by standardized scales, was significantly longer in patients randomized to the belzutifan arm compared to those in the everolimus arm. Also, patients in the everolimus arm had worse physical functioning scores. Dr. Neeraj Agarwal: Yes, Jeanny. In addition to the improved outcomes associated with belzutifan, patient-reported outcomes indicate better disease-specific symptoms and better quality of life among patients treated with belzutifan compared to everolimus. This is great news for patients with advanced renal cell carcinoma.  Now, Jeanny, can you please tell us about the two abstracts that reported longer follow-up of CheckMate 9ER and CheckMate 214 trials in untreated patients with advanced or metastatic renal cell carcinoma? Dr. Jeanny Aragon-Ching: Yes, Neeraj. So you are referring to Abstracts 362 and 363. Let's start with Abstract 362. This abstract reports the results after a median follow-up of 55 months in the CheckMate 9ER trial, comparing the combination of nivolumab and cabozantinib to sunitinib in patients with advanced RCC without any prior treatment, so first-line therapy. The primary endpoint was PFS per RECIST 1.1 as assessed by an independent central review. So there were key secondary outcomes including overall survival (OS), objective response rates, and safety. Consistent with prior analysis at a median follow-up time of 18.1 and 44 months, the combination of nivolumab and cabozantinib at a median follow up of 55.6 months continues to show a significant reduction in the risk of progression or death by 42% and in the risk of death by 23% compared to sunitinib.  Dr. Neeraj Agarwal: And Jeanny, what can you tell us about the efficacy results of this combination by IMDC risk categories? Dr. Jeanny Aragon-Ching: Similar to prior results in patients with intermediate to poor risk IMDC risk category, the combination treatment maintained significant efficacy and reduced the risk of progression or death by 44% and the risk of death by 27%. To put it simply, the update now shows a 15-month improvement in overall survival with the cabozantinib-nivolumab combination compared to sunitinib, which is amazing. Also, in patients with favorable IMDC risk group, which represented truly a small number of patients in the trial, there was a strong trend for improvement of outcomes as well. I would like to point out that no new safety concerns were identified. Dr. Neeraj Agarwal: So, it looks like the key message from this abstract is that with longer follow-up, the combination of nivolumab and cabozantinib maintains a meaningful long-term efficacy benefit over sunitinib, supporting its use for newly diagnosed patients with advanced or metastatic renal cell carcinoma.   Let's move on to Abstract 363, which compares nivolumab with ipilimumab to sunitinib in first-line advanced renal cell carcinoma. What would you like to tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Yes, Neeraj. The title of this abstract is "Nivolumab plus Ipilimumab versus Sunitinib for the First-Line Treatment of Advanced RCC: Long-Term Follow-Up Data from the Phase 3 CheckMate 214 Trial." In this abstract, Dr. Tannir and colleagues report outcomes with the longest median follow-up in first-line advanced RCC setting for any clinical trial. So the median follow-up now is about 18 months. The primary endpoints were OS, PFS, and objective response rates, as assessed by an independent review according to RECIST 1.1 criteria in the intermediate to poor risk IMDC risk group, which is the intent-to-treat (ITT) analysis, while secondary outcomes included the same outcomes in the ITT population of patients. Although the progression-free survival was similar in both arms, the combination of nivolumab-ipilimumab reduced the risk of death by 28% compared to sunitinib in the ITT population of patients. When stratifying the results by IMDC risk groups, the combination arm of nivolumab-ipilimumab showed significant improvement in the intermediate to poor risk group, but there was no difference in the favorable risk group. But in the study, no new safety signals were identified. Dr. Neeraj Agarwal: Thank you, Jeanny, for such a comprehensive description of the results of these two studies. I'd like to add that the median overall survival of patients with metastatic renal cell carcinoma in the ITT population in the CheckMate 214 trial has now reached 53 months, which would have been unimaginable just a decade ago. This is wonderful news for our patients. So the key takeaway from these two abstracts would be that immune checkpoint inhibitor-based combinations remain the backbone of first-line advanced renal cell carcinoma treatment.  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. This is wonderful news for all of our patients, especially for those who are being treated for first-line therapy.  Now, let's move on to the bladder cancer abstracts. We have two exciting abstracts from the UNITE database. What are your insights on Abstract 537, titled "Outcomes in Patients with Advanced Urethral Carcinoma Treated with Enfortumab Vedotin After Switch-Maintenance of Avelumab in the UNITE Study"? Dr. Neeraj Agarwal: As our listeners know, enfortumab vedotin is an antibody-drug conjugate that binds to a protein called Nectin 4 expressed on bladder cancer cells. In this abstract, Dr. Amanda Nizam and colleagues describe outcomes in 49 patients receiving third-line enfortumab vedotin after prior progression on platinum-based therapy and maintenance avelumab. At a median follow-up of 8.5 months, the median progression-free survival was 7 months and the median overall survival was 13.3 months with enfortumab vedotin in this treatment-refractory setting, the objective response rates were 54%. The message of this study is that enfortumab vedotin is an effective salvage therapy regimen for those patients who have already progressed on earlier lines of therapies, including platinum-based and immunotherapy regimens. Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for that comprehensive review.  I want to focus on another patient population in the UNITE database, which is the use of fibroblast growth factor receptor (FGFR) alterations. Can you tell us more about the sequencing now of erdafitinib and enfortumab vedotin in these patients with metastatic urothelial cancer, as discussed in Abstract 616? Dr. Neeraj Agarwal: Sure, Jeanny. As a reminder, erdafitinib is a fibroblast growth factor receptor kinase inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR2 or FGFR3 alterations after progression on platinum-based chemotherapy. However, the optimal sequencing of therapies in these patients is unclear, especially with enfortumab vedotin being approved in the salvage therapy setting and now in the frontline therapy setting.  So in this retrospective study, all patients with metastatic urothelial carcinoma had FGFR2 or FGFR3 alterations. Dr. Cindy Jiang and colleagues report outcomes in 24 patients receiving enfortumab vedotin after erdafitinib, 15 patients receiving erdafitinib after enfortumab vedotin, and 55 patients receiving enfortumab vedotin only. This is a multicenter national study. Interestingly, patients receiving both agents had a longer overall survival in a multivariate analysis, regardless of the treatment sequencing, than patients receiving enfortumab vedotin alone or only with a hazard ratio of 0.52. The objective response rate of enfortumab vedotin in the enfortumab vedotin monotherapy arm was 49%. When these agents were sequenced, the objective response with enfortumab vedotin was 32% after erdafitinib and 67% when used before erdafitinib. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. I think these are important real-world data results, but I would like to point out that larger and prospective studies are still needed to confirm these findings, especially regarding the outcome of erdafitinib after enfortumab vedotin, particularly when the latter is used in the first-line setting. Dr. Neeraj Agarwal: I totally agree, Jeanny. Now, let's discuss some abstracts related to disparities in the management of patients with genitourinary cancers.  Dr. Jeanny Aragon-Ching: Sure, actually, I would like to discuss 2 abstracts related to disparities in patients with prostate cancer. So the first one, Abstract 265, titled "Patient-Provider Rurality and Outcomes in Older Men with Prostate Cancer." In this study, Dr. Stabellini, Dr. Guha and the team used a SEER Medicare-linked database that included more than 75,000 patients with prostate cancer. The primary outcome was all-cause mortality, with secondary outcomes included prostate cancer-specific mortality. The investigators showed that the all-cause mortality risk was 44% higher in patients with prostate cancer from rural areas who had a provider from a non-metropolitan area compared to those who were in a metropolitan area and had a provider also from a metropolitan area. Dr. Neeraj Agarwal: Those are very important data and highlight the healthcare disparities among the rural population with prostate cancer that still exist.  So what is your key takeaway from Abstract 267, titled "Rural-Urban Disparities in Prostate Cancer Survival," which is a population-based study? Dr. Jeanny Aragon-Ching: Of course. This abstract discusses, actually, a very similar issue regarding access to healthcare among rural versus urban patients. In this study, Dr. Hu and Hashibe and colleagues and team at the Huntsman Cancer Institute assessed all-cause death and prostate cancer-related death risk in a retrospective study in which patients with prostate cancer based on rural versus urban residencies looked at 18,000 patients diagnosed with prostate cancer between 2004 and 2017. 15% lived in rural counties. Similar to the prior abstract we talked about, patients living in rural areas had about a 19% higher risk of all-cause mortality and a 21% higher risk of prostate cancer-specific mortality in comparison to patients living in urban areas. Dr. Neeraj Agarwal: So Jeanny, we can say that both of these abstracts, led by different groups of investigators, highlight that patients with prostate cancer living in rural areas have inferior survival outcomes compared to those living in urban areas, and it is time to focus on the disparities experienced by the rural population with prostate cancer.  Dr. Jeanny Aragon-Ching: Yeah, absolutely Neeraj. I concur with your thoughts.  So, any final thoughts before we wrap up the podcast today? Dr. Neeraj Agarwal: Yes, before concluding, Jeanny, I want to express my gratitude for your participation and the valuable insights you have shared today. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today.   As we bring this podcast to a close, I would like to highlight the significant advances happening in the treatment of patients with genitourinary cancers during our upcoming 2024 ASCO GU meeting. Many studies featuring practice-impacting data will be presented by investigators from around the globe. I encourage our listeners to not only participate at this event to celebrate these achievements, but to also play a role in disseminating these cutting-edge findings to practitioners worldwide. By doing so, we can collectively maximize the benefit for patients around the world.  And thank you to our listeners for joining us today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.  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. Guest speakers express their own opinions, experience, and conclusions. Guest statements on the podcast do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers:     Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:      Dr. Neeraj Agarwal:       Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See the full write ups for today's episode at nascentmc.com/podcastHere are the highlights: Belzutifan (Welireg) for RCC: - FDA approved belzutifan (Welireg) for advanced renal cell carcinoma (RCC) following prior treatments with PD-1/PD-L1 inhibitors and VEGF-TKI. Belzutifan is an HIF-2α inhibitor, the first novel therapeutic class for advanced RCC since 2015. Approval based on phase 3 LITESPARK-005 study data, granted to Merck Inc. Pulse Field Ablation (PFA) system for AFib: - FDA approved PulseSelect PFA system for atrial fibrillation (Afib) treatment. PFA uses electrical pulses to ablate cardiac tissue without thermal energy, reducing adverse events. Medtronic Inc. received approval. Roflumilast 0.3% (Zoryve) for Seborrheic Dermatitis: - FDA approved roflumilast foam 0.3% (Zoryve) for seborrheic dermatitis in individuals aged 9 and older. This is the first drug with a new mechanism of action for seborrheic dermatitis in over two decades. Approval supported by positive results from the STRATUM phase 3 trial, granted to Arcutis Biotherapeutics, Inc. Eflornithine (Iwilfin) for Neuroblastoma: - FDA approved eflornithine (Iwilfin) to reduce the risk of relapse in high-risk neuroblastoma patients. Eflornithine inhibits ornithine decarboxylase, reducing cell growth. Approval based on multi-site study results and granted to US WorldMeds, LLC. Isavuconazonium Sulfate For Pediatric Patients: - FDA approved isavuconazonium sulfate (Cresemba) for invasive aspergillosis and mucormycosis in pediatric patients. Provides an alternative to eye drops for glaucoma treatment, offering continuous delivery of travoprost. Approval based on Phase 3 trials and plans for label change, granted to Glaukos. Augmented Reality Smart Glasses Technology: - FDA approved NuLoupes augmented reality smart glasses with 3D stereoscopic imaging for dentistry and medicine. Offers live 3D stereoscopic imaging and plans to ship developer kits in 2024. Approval granted to NuEyes. OneRF Ablation System for Parkinson's: - FDA cleared the OneRF Ablation System for neurosurgical procedures in Parkinson's disease and other neurological conditions. Designed to capture electrical activity and selectively destroy brain tissue. Launch planned by NeuroOne in the first half of 2024. Pimicotinib For Tenosynovial Giant Cell Tumor: - FDA granted fast track approval to pimicotinib for the treatment of tenosynovial giant cell tumors. Demonstrated an overall response rate of 87.5% in a Phase 1b trial. Manufactured by Abbisko and commercialized in partnership with Merck. NDA for MDMA-Assisted Therapy for PTSD: - NDA submitted for MDMA in combination with psychotherapy for PTSD, aiming to be the first psychedelic-assisted therapy approved for PTSD. Submission by MAPS Public Benefit Corporation based on positive Phase 3 clinical trial results. Requested Priority Review of the NDA.

Have you considered oxygen as being part of YOUR solution for fixing leaky gut? Intestinal permeability (leaky gut) is a major issue, driving up inflammation in the body.    Leaky gut is also at the root of autoimmune conditions (eczema, cirrhosis, lupus, and rheumatoid arthritis – to name a few). It is something that the wellness world is trying to solve from several approaches.   Today's guest is one such member of the natural health and wellness world: health engineer and gut health specialist Steven Wright. Steven has created a wide range of products to keep your gut healthy, all of which can be found on his website, healthygut.com.   Steven has been doing some amazing research on delivering oxygen to our guts to strengthen our intestinal lining and heal up some of the 'tight junctions' that develop over time. He is at the cutting edge of gut health research and his approach to how we consider the entire environment of our gut is one that will resonate with fans of Dr. Jockers and his holistic approach to health.    This episode is an absolute must-listen for anyone dealing with chronic auto-immune conditions. So please take the time to share it with them; you never know when you may save or improve someone's life with a new approach to a health problem they may be struggling with.    This is valuable information that can give you a 'leg up' on your wellness journey. Please join us and leave us a five-star review along the way!   In This Episode:   Introduction to Steven Wright What are some of the biggest mistakes people are making in terms of treating leaky gut? Why we shouldn't only focus on 'tight junction integrity' Understanding immune dysfunction What happens when expensive supplements don't work? Appreciating that different tissues have different needs  Why is oxygen so important? What are HIFs? Is there a way to test your HIF levels? What are some strategies to improve your gut's microbiome diversity? What happens when you replace Butyric Acid as a supplement? Where do stomach acids and enzymes fit in the hierarchy of gut support? How probiotics help with immune system regulation When do you introduce probiotics? What does apple cider vinegar do? When to go in the opposite direction to find your gut solution Unpacking the role of glyphosate (herbicide) on leaky gut syndrome Addressing our overall toxic environment  What is the key to getting Butyric Acid deep into our system? What kind of results is Steven Wright getting with Tributyrin-X? The importance of low oxygen environment in our gut "Just keep going!" - final words of inspiration This podcast is sponsored by ShopC60.com. C60 is a powerful, Nobel Prize-winning antioxidant, that helps to optimize mitochondrial function, fights inflammation, and neutralizes toxic free radicals!   I'm a big fan of using C60 in conjunction with your keto and intermittent fasting lifestyle to support your immune system, help your body detox, and increase energy and mental clarity.    My favorite C60 products for Keto & IF lifestyles include C60 Purple Power in Organic MCT Coconut Oil (can add this to your coffee) and their delicious Sugar-Free C60 Gummies (made with allulose and monk fruit)!   If you are over the age of 40, and you'd like to kick fatigue and brain fog to the curb this year, visit shopc60.com and use the coupon code “JOCKERS” for 15% OFF  and start taking back control over your health today!   When it comes to gut health, bone broth is one of my ‘go to' items I add to my diet. But, not all collagen is created equal. Many brands use poor-quality bones and heating methods that remove all of the potent benefits of collagen.    That is why I choose to use Paleovalley Bone Broth Protein Powder, you can get all the gut healing benefits without the mess from a company that uses only 100% grass-fed and finished cows and is not processed with high heat or extracted with harmful chemicals.  There are no fillers, flow agents, or added flavors. There is only ONE ingredient in this product and it's bovine bone broth protein. Hurry and grab yours from Paleovalley.com     “If you don't have the right environment for the gut to behave, you can't expect it to behave correctly" - Steven Wright   Subscribe to the podcast on: Apple Podcast Stitcher Spotify PodBean  TuneIn Radio   Resources: Shop Carbon 60 - Use the coupon code "JOCKERS" for 15% OFF your first order in all their products! paleovalley.com/jockers   Connect with Steven Wright: Website - https://healthygut.com/   Connect with Dr. Jockers: Instagram – https://www.instagram.com/drjockers/ Facebook – https://www.facebook.com/DrDavidJockers YouTube – https://www.youtube.com/user/djockers Website – https://drjockers.com/ If you are interested in being a guest on the show, we would love to hear from you! Please contact us here! - https://drjockers.com/join-us-dr-jockers-functional-nutrition-podcast/

In this podcast, UROONCO RCC associate editor Dr. Teele Kuusk (GB) talks with medical oncologist Prof. Laurence Albiges (FR), Head of the Department of Oncology at Gustave Roussy, about her abstract: Belzutifan versus everolimus in participants with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomised open-label phase III LITESPARK-005 study.Prof. Albiges discusses the study results she presented at ESMO 2023. LITESPARK-005 established HIF-2a inhibition as a novel therapeutic mechanism of action in advanced clear cell RCC. Belzutifan demonstrated a statistically significant improvement in progression-free survival (PFS) and objective response rate versus everolimus.LITESPARK-005 is the first positive phase 3 study in patients with advanced kidney cancer following immune checkpoint and anti-angiogenic therapies.Prof. Albiges also answers a question about why everolimus was used as a comparator in this trial. Looking at the future, she shares her vision of how Belzutifan (the new HIF inhibitor) can be used for metastatic kidney cancer patients.Lastly, Prof. Albiges talks about what trials are ongoing that will position Belzutifan on the treatment line. Belzutifan is currently being studied in combination in second-line, first-line, and adjuvant settings in phase 3 studies.

In this week's New FDA Approval's podcast episode, Dr. Emma Hitt Nichols discusses the latest FDA approvals from September 18, 2023 – September 22, 2023.  Please check back every Monday morning so that you can stay up to date.  Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See more details summaries and links to prescribing information at nascentmc.com/podcast Here are the highlights: Jardiance (empagliflozin) for CKD  The FDA has approved Jardiance, an SGLT2 inhibitor, for patients with end-stage kidney disease, speciifically to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. The approval is based on the EMPA-KIDNEY phase 3 trial, demonstrating a significant reduction in kidney disease progression and cardiovascular death compared to a placebo.  Welireg (belzutifan) for Advanced Renal Cell Carcinoma The FDA granted Priority Review for Merck's Welireg for advanced renal cell carcinoma post other treatments. Welireg, a HIF-2α inhibitor, is being evaluated in the LITESPARK-005 trial, where it was compared with everolimus for advanced RCC treatment post PD-1/L1 or VEGF-TKI therapies. Tevimbra (tislelizumab) for Esophageal Squamous Cell Carcinoma The FDA is reviewing an application for Tevimbra for treating advanced or metastatic esophageal squamous cell carcinoma. Supported by the phase 3 RATIONALE 306 study, the drug improves overall survival rates when combined with chemotherapy in these patients. Neffy Epinephrine Nasal Spray The FDA rejected the approval of Neffy, a needle-free nasal spray for allergic reactions. Despite a positive Advisory Committee vote, the FDA demands further testing. ARS Pharmaceuticals plans to re-submit its application and appeal the decision in 2024.  Intro and outro music Garden Of Love by Pk jazz Collective

BUFFALO, NY- September 20, 2023 – A new editorial paper was published in Oncotarget's Volume 14 on September 15, 2023, entitled, “Potential repurposing of DPP4 inhibitors for target therapy resistance in renal cell carcinoma.” In their new editorial, researchers Kuniko Horie and Satoshi Inoue from Saitama Medical University and Tokyo Metropolitan Institute for Geriatrics and Gerontology discuss renal cell carcinoma (RCC) — a major adult kidney cancer, which is often incidentally discovered as an asymptomatic disease on imaging in the developed countries. RCC has the most fatal disease among urological cancers, as a recent 5-year relative survival rate in the U.S. (2009–2015) is less than 80%. While RCC is known as a cancer resistant to chemo- and radio-therapies, the prognosis of RCC has been remarkably improved after the clinical application of tyrosine kinase inhibitors (TKIs) and immunotherapy. The rationale for the efficacy of TKIs in RCC is mainly based on the angiogenetic status, particularly in clear cell RCC (ccRCC) that is the most common type of RCC (70–75% of RCC), in which the loss of function mutation of Von Hippel-Lindau (VHL) tumor suppressor gene activates hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) pathways. The first-line TKIs that predominantly target VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) (e.g., sunitinib and sorafenib) have been clinically used since late 2000s, and the second-line TKIs such as cabozantinib, which targets more receptor tyrosine kinases including MET and TAM kinases as well as VEGFR, have been further applied to the treatment of advanced RCC since early 2010s in which the first-line TKIs are ineffective. “In our recent study, we established a panel of patient-derived ccRCC spheroid cultures with the enhancement of cancer stemness gene signature including DPP4 [9]. Focusing on TKI sunitinib sensitivity, we demonstrated that DPP4 inhibition increased sunitinib efficacy in DPP4-high RCC spheroids and DPP4 was upregulated in sunitinib-resistant RCC cells.” DOI - https://doi.org/10.18632/oncotarget.28463 Correspondence to - Satoshi Inoue - sinoue07@gmail.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28463 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, renal cell carcinoma (RCC), tyrosine kinase inhibitor (TKI), Dipeptidyl peptidase IV (DPP4), drug resistance, drug repurposing About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Drs. Pedro Barata and Naomi Haas discuss the emergence of clinical trials investigating triplet combinations in advanced renal cell carcinoma, factors that influence treatment decisions, strategies to personalize therapies in the frontline setting, including response-adaptive treatment strategies, and the use of biomarkers such as gene expression analysis to guide initial therapy. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata. I'm your guest host of the ASCO Daily News Podcast today. I'm an associate professor of medicine and also a GU medical oncologist at University Hospital Seidman Cancer Center, Case Western University in Cleveland, Ohio. I'm also an associate editor for the ASCO Educational Book. Today I'm really delighted to welcome Dr. Naomi Haas, the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center and professor of medicine at the University of Pennsylvania.  Welcome, Dr. Haas. Dr. Naomi Haas: Thank you, Dr. Barata. It's a pleasure to be interviewed. Dr. Pedro Barata: Thank you. As you know, we've seen significant strides in the frontline treatment for patients with advanced clear cell renal cell carcinoma (RCC), and there are multiple doublet regimens that are now the standard of care for those patients. The goal for us to chat today is to discuss the emergence of clinical trials that are really investigating triple combinations and the factors that influence treatment decisions around triplet combinations for patients with advanced renal cell carcinoma. I want to congratulate you for the great work that you did in a recently published article in the 2023 ASCO Educational Book. So thank you for your contributions. And just before we get started, I just want to highlight that our full disclosures are available in the transcript of this episode. So, Dr. Haas, again, it's great to have you. Thank you for taking the time. Let me get started. So, we know that there are multiple standard of care doublet regimens, all of them immunotherapy-based combos, and they usually include 1 checkpoint inhibitor or 2, such as ipilimumab plus nivolumab or a combination of an immune checkpoint inhibitor with a VEGF TKI. And we have a number of examples like that. Can you tell us about the trials that have emerged exploring triplet therapies in the first-line setting for patients with advanced RCC? Dr. Naomi Haas: Sure, and I'm going to focus just on triplet therapies that are just about ready to go. But as you know, Pedro, there are probably many different combinations that we'll see in the future. Some of the combinations that have already been conducted as clinical trials include combinations of VEGF receptor tyrosine kinase inhibitors along with immune checkpoint inhibitors. I'll highlight one which was batiraxcept plus cabozantinib and nivolumab, and it's a combination of VEGF inhibitor, immune checkpoint inhibitor, and also an AXL inhibitor. So, most of these capitalize on other vulnerabilities with renal cell carcinoma.  So, as you said, they build on the tyrosine kinase inhibitor pathway or on the immune checkpoint inhibitor pathway. Some of them are combining drugs such as CDK inhibitors. There was axitinib plus nivolumab plus palbociclib trial that is getting ready to launch. Others are combining the use of belzutifan, which is a HIF inhibitor in combination with VEGF inhibitor and immune checkpoint inhibitor. There are a couple of those that are ongoing, one of them looking at combinations with lenvatinib. And I think there are also trials getting ready to launch that are using it in combination with cabozantinib and nivolumab.  Additionally, another very interesting direction is trying to affect the gut microbiome. And there was a clinical trial presented by Dr. Monty Pal at the gut microbiome session at ASCO, which combined CBM-588, which is a probiotic, in combination with cabozantinib and nivolumab. And that showed an improvement in progression-free survival compared to the combination of cabozantinib and nivolumab alone. And previously there was work published using CBM-588 in combination with ipilimumab and nivolumab. So that's an area of high interest to patients. But most of these combinations capitalize on either vulnerabilities, signs of resistance in pathways or in adding other pathways that have previously been unaddressed in renal cell carcinoma, and are combined with pathways that we know are effective. Dr. Pedro Barata: Wow, that's a fantastic overview of some of the approaches being considered in the frontline, so thank you for that. And actually to your point, some of them we've seen some data, others more later stages of development. So with that in mind, we also know that we have on one side of the story we have how much of these combos of triplets can actually be effective and help patients. From the other perspective is about tolerability, treatment options, and patient health. They're both very important considerations.  Can you tell us a little bit about the safety profile of these triplet combos? I know we're talking about many different things. The microbiome triplet has a different safety profile than perhaps a combination with a TKI and different checkpoints, for instance. Can you tell us a little bit about what we expect from the safety profile when we start to combine these therapies in the upfront setting?  Dr. Naomi Haas: Sure. I think 2 of the very tolerable triplet regimens have been the combination of the CBM-588 in combination with ipilimumab and nivolumab. Really in those combinations, the authors at least have demonstrated that there has not been a great difference between the two study arms of either the doublet or the doublet in combination with the CBM-588 trial. And that's based on basically changing the bacterial flora of the gut. The Avera trial, which was using the AXL inhibitor in combination with cabozantinib and nivolumab, also seems to have a very tolerable safety profile. Now, this trial was not compared to sort of a standard of care arm, so it's a little bit difficult. A standard of care arm that I would have considered for this clinical trial would have been to use either cabozantinib alone or cabozantinib with nivolumab. Instead, this was more of a dose-finding protocol. So, more work needs to be done with that, but the side effects of that combination additive to what we already know seem to be just infusion reactions from the AXL inhibitor.  The trial that got the most attention so far has been COSMIC-313, which was combining cabozantinib with ipilimumab and nivolumab upfront. And of course, the concern with this triplet combination was that there was more hepatotoxicity seen and it was difficult to know whether the hepatotoxicity was from the combinations of the immune checkpoint inhibitors or the use of the cabozantinib. And although the trial showed an improvement in progression-free survival, it did not show as many complete responses as the comparator arm. And the other concern was that there was quite a bit of dropout due to toxicity. And of course, we don't have the overall survival endpoint for that trial yet. Dr. Pedro Barata: Great, thank you for that. I agree completely. We've seen many different safety profiles with these different triplets.  Let me touch base on a slightly different topic, and that has to do with what kind of strategies can we think to personalize treatment for clear cell RCC in the frontline. And this is not necessarily applicable only to triplet therapy. There are also some efforts with doublets, but the goal is, I would argue, is response adaptive treatment strategies or even the use of upfront biomarkers such as gene expression analysis, for example, to help us guide initial therapy. Can you give us an idea what your thoughts are about what is coming? What do you think the future will look like in terms of developing this like a biomarker-based approach? What kind of factors or markers we can use to select who gets what in the frontline setting? Dr. Naomi Haas: Sure. So, I'll just highlight ahead of that that one important biomarker that we're already using is the IMDC criteria, which I think if that algorithm had not been developed, we would be struggling a lot in renal cancer and that's, of course, the algorithm that uses the thing such as performance status, hemoglobin, calcium, and time for the development of metastatic disease as well as the neutrophil count and the platelet count. And that has helped us divide categories of patients with clear cell renal cell carcinoma into poor risk, intermediate risk, or favorable risk categories. And that was recently validated in the immune therapy combinations that were previously been validated just in VEGF inhibitor therapies.  But the other useful, let's start with clinical tools that I think are going to be very important are the health-related quality of life tools which primarily measure things such as functional health, as well as toxicity. And one of these is the FKSI-19 score which captures most renal disease-related symptoms, treatments, side effects, and functional well-being. And this has been implemented in some trials and are looked at over time whether the patient's functional status improves. And patients who are responding to therapies generally will improve as far as their overall well-being. Although that can be difficult as a tool because if patients are experiencing toxicity, those signs might not be apparent. But that's one tool that's being used.  Now, people, both patient advocates and patients, have pointed out that it's very hard to use a tool like this in real life to implement in clinic, but there are efforts being carried out to make these tools a little bit easier so that people can use them day-to-day. So, I can see that being implemented more often.  The others have to do with response assessments, and I think it's very important to look at immune-related responses which kind of builds on the resist response, but it uses two dimensions of measurement as opposed to one dimension of measurement. And looking at those, we know now that patients who have what we call a deep response, so something better than a 75% shrinkage or even a 90% shrinkage in a very short period of time tend to be those patients who behave like patients who have complete responses. And both progression-free survival and overall survivals seem to be going in a very encouraging way looking at these tools so you could see that this tool could be implemented in real life with treating a patient and if they have a very deep response quickly, you can feel, the physician or the APP, could be very confident that the patient is going to do well for a long period of time. I think the tools that we're waiting for the most, however, are as you said, the biomarker tools. And this is where we still have a lot of work to do, but one example of this is the transcriptomics which has been conducted in both the atezolizumab-based trials such as the IMmotion trials, and also to some extent with the JAVELIN trials, the avelumab and axitinib trials. And this goes back to looking at the tissues sample and looking at transcriptomics which show mRNA expression as well as some alterations in some of the important genes such as BAP1 and PRBM1.  And those tools have been implemented, especially in the IMmotion trial, there were 7 clusters identified, and two of the clusters are groups of patients whose tumors have transcriptomics that indicate that they would respond well to a VEGF inhibitor. And a couple of them also showed very good responses to immune checkpoint pathways. There were additional pathways which suggested that patients wouldn't be responsive to either of these. And there is a trial called OPTIC that is funded by the Department of Defense (DOD) which is currently applying these transcriptomics, and then assigning patients to get either a VEGF IO therapy combination or a dual immune checkpoint inhibitor combination, based on their transcriptomics.  And I think what everybody would really like to see is, number 1, that these transcriptomics consistently bear out that there isn't irregularity in using these as predictors. So, they do need to be validated. But I think if there was a quick and easy way to do this, to assign patients to therapies based on these profiles, that would perhaps go a long way in predicting what therapy a patient should start with.  Another useful tool is the development of artificial intelligence. And there are a number of companies that are looking at these tools. We're implementing this retrospectively in the ASSURE trial, which was the adjuvant seraphinib synontib or placebo trial, for patients at high risk for RCC. And we're working with a company to identify, using AI, looking at the slides. And I think that if these kinds of techniques, which are already being used in prostate cancer, are something that can be developed, then what I could see in the future is that a patient's slide could be tested very quickly, and that that might also indicate things that perhaps we can't see under the microscope, as far as either a response to treatment or a risk. So, you could use that in the adjuvant setting to predict whether a patient might need adjuvant therapy or not. So I can see those being implemented.  And then the third is looking at cell-free DNA. And there are many different mechanisms that have been tested in other solid tumors, using either circulating tumor DNA or cell-free DNA. Now, the circulating tumor DNA seems to be a little bit more difficult to assess in metastatic kidney cancer because it doesn't have the mutational burden and doesn't seem to have as many mutations and things floating around that can be captured. However, cell-free DNA, which has the capability of measuring DNA methylation profiles, does seem to be showing some promise, and there have been some publications.  So this has also been tested in cancers of all stages and can be measured in both the plasma and in the urine. And that could be another helpful tool that needs to be validated, but that could be used to start a patient on treatment. And if the amounts of cell-free DNA went down with therapy, that could be a good indication, perhaps in advance of imaging, that a patient is doing well with therapy.  So those are some examples that I see potentially being used in the future to help direct therapy, provided that we can make these tools, that we can validate these tools, and secondly, that these tools are relatively inexpensive and that they're nimble, that they could be used right away, that it wouldn't take a long time to get the results back to help guide. Dr. Pedro Barata: For sure. I couldn't agree more. What a masterclass of all the emerging tools that are being investigated in RCC, this is fantastic.  So, I guess maybe one last question before I let you go. We have now a number of doublets, we have perhaps a triplet, if not more. If you were to guess, who do you think will be the ideal population for a triplet therapy? Some, in addition to all the tools you mentioned, maybe sarcomatoid features, etc. that might be part of the AI complement to what you mentioned earlier. But if you were to guess, do you think that 5 years from now, we're going to be offering a triplet therapy, whatever that triple therapy might be, to everybody, to certain populations? What can you tell us to help us predict what might happen in the near future to make us think about a thoughtful, shared decision-making process and try to predict who might be the ideal population for triplet therapy? Dr. Naomi Haas: So, I don't think we're going to use triplet therapy in everybody. And in fact, I hope we don't use triplet therapy in everybody because I have patients who have responded to single-agent nivolumab and remained in a continuous CR many years after they were treated that way. And I have other patients who really progressed very rapidly or relapsed very quickly after doublet therapy combinations. So, I think that what I would see in the future would be using the triplet therapy combinations in the challenging patients, the patients who we know we're not getting as far along with the doublet approach. And that's really our challenge. And I would see that perhaps some of this transcriptomics which indicates that there are subsets of renal cell carcinoma which are not going to respond well to a VEGF inhibitor or to an immune checkpoint inhibitor, that those are areas where there might be other relevant pathways where maybe the signal isn't quite as good with– maybe they have some response, but not an optimal response. And then combining another pathway into that would be a way forward to achieve a complete response in those populations.  I also want to emphasize that it may be that triplet therapy isn't the way to go, but that triplet therapy can be more of an adaptive design where a doublet therapy is started, and then the third drug, a triplet, is added at a later time. And an example of that is PDIGREE, which is the combination of ipilimumab and nivolumab. And then following imaging, patients are assigned, depending on the response, to get either cabozantinib alone, cabozantinib with nivolumab, or to continue on just nivolumab alone. And that might be a better way to address toxicity. But some of these other triplet combinations, one could also see- you could start, for example, with ipilimumab and nivolumab, and if they were having a response but you wanted to heighten the response, maybe adding the CBM-588 as an adaptive response or adding a CDK inhibitor, but sort of staggering the combination so that you spare patients some of the toxicity. So, I think all of those approaches need to be tested. Dr. Pedro Barata: That is fantastic. Dr. Haas, this is an incredible podcast. You did highlight several triplet combinations that are currently under investigation. You highlighted very, very important ongoing clinical trials. You touched base on what the future might bring as far as tools that might help us decide or optimize patient selection. We talked about adaptive designs. So really outstanding work. And also, I think this reflects the fantastic work in the manuscript that you wrote in the 2023 ASCO Educational Book.  So, thank you so much, Dr. Haas, for the incredible work that you have done and you continue to do in the GU field, and for taking the time to share your insights with us today on the ASCO Daily News Podcast. It's truly been a pleasure to chat with you today. Dr. Naomi Haas: Thank you.  Dr. Pedro Barata: Thank you again. And thank you also to our listeners for joining us today. Really happy with talking about this topic with Dr. Haas. You can also find links to the studies that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  So again, it has been a privilege to be here today with Dr. Haas. Thank you for joining us and have a good day.   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. Pedro Barata @PBarataMD Dr. Naomi Haas   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. Pedro Barata: Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon Speakers' Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.):  Blueearth, AVEO, Pfizer, Merck   Dr. Naomi Haas: Consulting or Advisory Role: Pfizer, Merck Sharp & Dohme, Calithera, Eisai, Exelisis, AVEO, Roche/Genentech Expert Testimony: Lilly

In this episode we discuss: Why uncoupling is harmful in certain contexts and how PUFA cause constant, low-level uncoupling The involvement of uncoupling, mitochondrial biogenesis, autophagy, heat shock proteins, and hypoxia-inducible factors in the stress response How stress prevents our mitochondria from effectively producing energy How chronic stress causes insulin resistance, high blood pressure, weight gain, depression, and cardiovascular disease How sugar and fat cravings result from stress and why listening to them is beneficial How adaptations to stress get passed on through generations   Sign up for the Free Energy Balance Mini-Course here: https://jayfeldmanwellness.com/energy   Click here to check out the show notes: https://www.jayfeldmanwellness.com/ep-94-how-stress-crashes-your-metabolism-why-hormesis-is-not-the-answer-stress-mitochondria-part-2/   Timestamps: 0:00 – intro  2:59 – the details of how mitochondrial respiration can become disrupted, especially from glucocorticoids 6:05 – the short-term effects of catecholamines 8:34 – why uncoupling is harmful in certain contexts and how PUFA cause constant, low-level uncoupling 14:40 – the protective effects of uncoupling as a part of the stress response 20:08 – the role of cytokines (TNF-alpha, IL-1, IL-6, heat-shock proteins, NF-kB, HIF) in the stress response 37:33 – the effect of acute stress on energy production in mitochondria 45:18– the effect of chronic stress on energy production in mitochondria 48:15 – how stress drives degeneration and the evidence for increased activity of hormetic pathways (including effects like mitochondrial biogenesis and autophagy) in degenerative states 1:05:24 – the relationship between mental health, mood, and metabolic function 1:10:21 – how adaptations to stress get passed on through mitochondrial DNA 1:18:32 – how to best improve mitochondrial function and our health

Dr. Ralph W. Moss and son Ben discuss the healing and preventive properties of the readily available, inexpensive and delicious, humble little parsley plant.   Join us for another fascinating journey as we dive 'Beyond the Garnish' into the remarkable world of parsley and its component, Apigenin. This humble herb, often relegated to the sidelines of our plates, holds an impressive secret - the potential to significantly impact the fight against cancer. Program Notes: For more information on cancer-fighting foods and supplements, please visit our website: https://www.themossreport.com 5 Defenders Mushroom Blend https://shop.realmushrooms.com/products/organic-mushroom-blend-capsules?ref=391 “A comprehensive self-help plan for cancer includes medicinal mushrooms. They are indispensable”. – Ralph W. Moss, PhD Olive Oil From the Raw https://www.olivefromtheraw.com/?aff=2 “A study of over 1,000,000 people shows that daily consumption of 2 Tbsp of high quality, extra virgin olive oil that contain polyphenols, results in a 30-40% decrease in cancer incidents.” – Ralph W. Moss, PhD For Dr. Moss' recommended products list, please visit https://www.themossreport.com/recommended-products/ The full scope of research on apigenin and cancer: https://pubmed.ncbi.nlm.nih.gov/?term=apigenin+cancer The Indian review article: Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models https://pubmed.ncbi.nlm.nih.gov/35752426/ The German clinical trial: Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703843/ Recommended parsley intake: Approximately 0.79 tablespoons or 2.37 teaspoons of chopped fresh parsley would provide 10 mg of apigenin. TAKE about one tablespoon OR THE EQUIVALENT AMT. OF DRIED PARSLEY (SEE BELOW) TWICE PER DAY. For 0.69 grams of dried parsley flakes: 0.69 grams / 0.8 grams per teaspoon ≈ 0.86 teaspoons So, approximately one teaspoon 0.86 teaspoons of dried parsley flakes would provide 10 mg of apigenin. OR TAKE THIS TWICE PER DAY. NOTE: PATIENTS IN THE GERMAN STUDY ALSO RECEIVED EGCG (GREEN TEA) AT THE SAME TIME. Based on the average amount of EGCG in one gram of Japanese Sencha green tea leaves (47.3 milligrams), and assuming that you're using one teaspoon (about 2.5 grams) of tea leaves to brew 6 ounces of tea, you can expect to get around 118.25 milligrams of EGCG in your cup of tea. A short bibliography on apigenin and cancer: Shukla S, Gupta S. Apigenin: a promising molecule for cancer prevention. Pharm Res. 2010;27(6):962-978. Salehi B, Venditti A, Sharifi-Rad M, et al. The therapeutic potential of apigenin. Int J Mol Sci. 2019;20(6):1305. Chen AY, Chen YC. A review of the dietary flavonoid, apigenin, on cancer prevention and treatment. Curr Med Chem. 2013;20(19):2570-2581. Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 2005;19(3):342-353. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. Kim BR, Seo HS, Ku JM, et al. Apigenin inhibits cancer stem cell-like phenotypes in human glioblastoma cells via suppression of c-Met signaling. Phytother Res. 2016;30(5): 800-807. Lu L, Sun T, Chen X, et al. Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through the AKT/GSK-3β/Snail signaling pathway. Oncol Rep. 2016;35(1):369-374. Lu Z, Xu S, ER P, et al. Apigenin inhibits the self-renewal capacity of human ovarian cancer SKOV3-derived sphere-forming cells. Mol Med Rep. 2015;11(4): 2850-2856. Wang J, Wu J, Zhang X, et al. Apigenin suppresses the growth of colorectal cancer cells by targeting Twist-mediated epithelial-mesenchymal transition. Mol Med Rep. 2018;17(5): 7305-7310. Yao J, Zhao L, Zhao Q, et al. Apigenin inhibits ovarian cancer stem cell-like properties through the modulation of the Twist1/TGF-β1/Smad3 pathway. Oncol Rep. 2016;36(1): 512-520. For Dr. Moss' Red, Green, and Green Tea Smoothie recipes, visit The Moss Report. These smoothie recipes are just some examples of how you can incorporate natural compounds with potential health benefits into your diet.

Dr. Clovis Palmer is an Assistant Professor at Tulane University. He talks about how HIV hijacks metabolic processes and the role of HIF-1α in HIV infection. He also discusses using non-human primates to study SARS-CoV-2 and other viruses.

Liesl Janssens is a PhD Student at the laboratory of Toxicology at Ghent University. She joins us again in this episode to give us an update on her research focused on developing new detection methods for Hypoxia-inducible factor (HIF) stabilizers. She also discusses recent work that she and her colleagues have been doing to characterize and detect cannabinoids, opioids, and psychedelics using similar activity-based assays.

A new research paper was published in Oncotarget's Volume 14 on February 2, 2023, entitled, “Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC).” TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50–60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. In this recent study, researchers Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Taylor Powell, Landon Goodreau, Emily K. Daniel, Xiaohua Rong, Tara Moore-Medlin, Alok R. Khandelwal, and Cherie-Ann O. Nathan from LSU-Health Sciences Center investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. “The role of mTOR inhibitors (mTORi) as potent growth inhibitory and antiangiogenic/anti-lymphangiogenic agents in HNSCC is well established [18]. Moreover, mTORi significantly suppressed baseline invasiveness of endothelial and HNSCC tumor cells [19]. However, the underlying molecular mechanisms for mutant p53 protein-mediated activation of the mTOR pathway which drive the oncologic processes in HNSCC are yet to be elucidated.” Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. “Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.” DOI: https://doi.org/10.18632/oncotarget.28355 Correspondence to: Cherie-Ann O. Nathan - cherieann.nathan@lsuhs.edu Keywords: TP53 mutant, HNSCC, angiogenesis, everolimus, mTOR About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Porsche's synthetic gasoline factory comes online today in Chile | Ars Technica (01:07) A Chilean startup called Highly Innovative Fuels officially opened its first synthetic gasoline production facility.  Result of a collaboration between the automaker Porsche, Siemens Energy, Exxon Mobil, Enel Green Power, the Chilean state energy company ENAP, and Empresas Gasco.  What is synthetic fuel or synfuel? A feedstock is a raw material that is used as a source of energy or as a starting material for the production of a product. A type of fuel that is made from synthetic hydrocarbons Typically produced from coal, natural gas, or biomass through a process known as the Fischer-Tropsch process.  Synthetic fuel is a direct drop-in for pump gasoline Initially, the site will produce around 34,000 gallons (130,000 L) a year, Scaling up to 14.5 million gallons (55 million L) a year by 2024. Plans to increase that tenfold to 145 million gallons (550 million L) a year by 2026.  The site, located in Punta Arenas in Southern Chile, will use wind to power the processThe area sees high winds roughly 270 days a year, and a wind turbine can expect to produce up to four times as much energy as one in Europe. Conversion process of the plant:The e-fuel plant will use wind power to electrolyze water into hydrogen and oxygen.  The hydrogen is then combined with carbon captured from the air or industrial sources to synthesize methanol. The methanol in turn can then be converted into longer hydrocarbons to be used as fuel. HIF has long-term plans to build out 12 synthetic fuel plants worldwide, including locations in the US and Australia, with a goal of each site capturing 2 million metric tons of CO2 per year.Could be an incentive for CO2 capture! It is NOT CHEAPAt current prices, it works out to around $8 per gallon ($2/L), although that obviously doesn't include any taxes or duties NASA Discovers Pair of Super-Earths With 1,000-Mile-Deep Oceans | SciTechDaily (08:24) Astronomers have uncovered a pair of planets that are water worlds unlike any planet found in our solar system.Slightly larger than Earth, they don't have the density of rock, but they are denser than gas giants in our solar system What are they made of? The best answer is that these exoplanets have global oceans at least 500 times deeper than the average depth of Earth's oceans, which simply are a wet veneer on a rocky ball. They orbit the red dwarf star Kepler-138, located 218 light-years away in the constellation Lyra.Called Kepler-138 c and Kepler-138 d Planets were initially found in 2014 with NASA's Kepler Space Observatory.  But with follow-up observations with the Spitzer and Hubble space telescopes they found that the planets must be composed largely of water.  The discovery was made by a team of researchers at the University of Montreal lead by Caroline Piaulet.By comparing the sizes and masses of the planets to models, the astronomers concluded that a significant fraction of their volume should be made of materials that are lighter than rock but heavier than hydrogen or helium. Most common being water.  The closest size comparison, say researchers, would be some of the icy moons in the outer solar system (i.e. Europa, Enceladus) that are also largely composed of water surrounding a rocky core. But don't expect the water to be the same as the water you see here. According to Piaulet:“The temperature in Kepler-138 d's atmosphere is likely above the boiling point of water, and we expect a thick dense atmosphere made of steam on this planet. Only under that steam atmosphere there could potentially be liquid water at high pressure, or even water in another phase that occurs at high pressures, called a supercritical fluid.” A supercritical fluid is a substance that is in a state between a gas and a liquid and exhibits unique properties that are intermediate between the two phases. (Not a pressure to be solid) Gene therapy cures kids with rare “bubble-boy” disease in new trial | New Atlas (12:18) A rare genetic disease, called Severe combined immunodeficiency (SCID), renders children without a functioning immune system from birth has been effectively cured by an experimental gene therapy. SCID is a collection of genetic diseases that result in impaired immune functions.  Informally known as the "bubble-boy" disease The study is reporting on the first 10 children treated with the therapy, all of whom are now healthy and living normal lives. The two most common forms of SCID – X-SCID and ADA-SCID – have been successfully treated with an experimental gene therapy.The patient's bone marrow stem cells are harvested, modified with a healthy copy of the targeted gene, and then infused back into their bodies. This form of gene therapy uses a modified virus to deliver its healthy gene payload. Sometimes cancerous side effects. Because those viruses can only enter a cell's nuclei when it's dividing they can potentially generate adverse side effects.  Many researchers have shifted to using modified lentiviruses as the optimal viral vector for gene therapies.Enter the nuclei of non-dividing cells meaning they should be safer and more effective. In 2021, a more long-term study tracking 50 children with ADA-SCID treated with lentiviral gene therapy found every subject was alive and healthy three years later. The 10 children in this latest study were treated for ART-SCID, which is an extremely rare version of SCID and difficult to treat. Over two years after the initial treatment all 10 children are reported as healthy and living normal lives. Jennifer Puck, co-lead investigator on the study, discusses the results:“All of the results are better than those previously seen with Artemis-SCID patients who received donor bone marrow transplants … Having patients in the trial achieve full T-cell immunity is outstanding. B-cell recovery takes longer, but so far it looks as if the patients also have a far better chance for B-cell reconstitution than they would with a regular bone marrow transplant. Successfully using less chemotherapy is also a big win, minimizing the harmful side effects of full dose busulfan in small infants.” Larger studies are needed (as always), but the results are extraordinarily promising, pointing to a future where this genetic disease can be cured soon after birth. Proof-of-concept drone flight delivers transplant lung to patient in Toronto | TechXplore (17:37) A team of researchers have demonstrated the feasibility of using drones to carry human organs for transplantation to nearby locales.  A drone carried a human lung donated by a deceased patient at one hospital in downtown Toronto, Canada, to another patient needing a new lung waiting in another hospital, also in downtown Toronto. This feasibility study was meant to test the use of drones for carrying donated organs on a regular basis.Drone used was the Chinese-made M600 Pro Added new electronics designed specifically for strong connectivity—the drone is steered on its path by a human pilot. Added a parachute, lights, several cameras, GPS trackers and a recovery system. Finally, they removed the landing gear and replaced it with a container box specifically designed to keep organs cool during transport. They had the drone carry objects from point to point, testing all of its features. After 400 such test flights, they deemed their drone ready The proof-of-concept flight:Took off from Toronto Western Hospital with the drone carrying a donated lung Flew to Toronto General Hospital, just two kilometers away The lung was delivered and safely implanted into the waiting patient.  The researchers suggest their approach can be used for short-distance transfers in densely populated areas, such as across a city, greatly reducing delivery time.Ground vehicles can take a lot of time due to congestion and unforeseen tie-ups. Blood test detects 'toxic' protein years before Alzheimer's symptoms emerge |  ScienceDaily (22:55) Seeds of Alzheimer's are planted years -- even decades – before the cognitive impairments surface that make a diagnosis possible. Amyloid beta proteins that misfold and clump together, forming small aggregates called oligomers. Those oligomers through a process scientists still do not understand become “toxic,” which then are thought of to cause Alzheimer's. University of Washington researchers have developed a laboratory test that can measure levels of amyloid beta oligomers in blood samples. Detected in the blood of patients with Alzheimer's disease But did not detect them in most members of a control group who showed no signs of cognitive impairment Their test, known by the acronym SOBA, did detect oligomers in the blood of 11 individuals from the control group.10 of these individuals had follow-up examinations where all were diagnosed years later with mild cognitive impairment or brain pathology consistent with Alzheimer's disease.  Senior author professor Valerie Daggett stated:“What clinicians and researchers have wanted is a reliable diagnostic test for Alzheimer's disease -- and not just an assay that confirms a diagnosis of Alzheimer's, but one that can also detect signs of the disease before cognitive impairment happens. That's important for individuals' health and for all the research into how toxic oligomers of amyloid beta go on and cause the damage that they do … What we show here is that SOBA may be the basis of such a test." In the study, the team also showed that SOBA easily could be modified to detect toxic oligomers of another type of protein associated with Parkinson's disease and Lewy body dementia. Dagget stating:"We are finding that many human diseases are associated with the accumulation of toxic oligomers that form these alpha sheet structures … Not just Alzheimer's, but also Parkinson's, type 2 diabetes and more. SOBA is picking up that unique alpha sheet structure, so we hope that this method can help in diagnosing and studying many other 'protein misfolding' diseases."