Podcast appearances and mentions of Steve Rosenberg

Hosted by Jane Pauley. In our cover story, Elaine Quijano reports on how an Army wife helped change military culture regarding the notification of next of kin about casualties. Also: Robert Costa sits down with Pulitzer Prize-winning novelist Anne Tyler; Kris Van Cleave explores the centenary of Delta Air Lines; Elizabeth Palmer interviews Steve Rosenberg, the BBC's "Man in Moscow"; Tracy Smith talks with music producer David Foster, the composer behind the new Broadway musical “Boop!”; and “Sunday Morning” offers previews of the summer's most anticipated movies, music, books and museum exhibits. To learn more about listener data and our privacy practices visit: https://www.audacyinc.com/privacy-policy Learn more about your ad choices. Visit https://podcastchoices.com/adchoices

After a two-hour phone call on Monday, Donald Trump and Vladimir Putin came to very different conclusions about what was agreed. The US said ceasefire negotiations between Moscow and Kyiv would start “immediately.” The Kremlin meanwhile, said there were no deadlines to move towards peace. On this episode the BBC's Russia editor Steve Rosenberg tells us about the reaction to the call in the Russian press. And - as Europe prepares to level further sanctions - Robert Fox, defence editor at the Evening Standard, tells us the West needs to prepare for a longer term conflict.Today's episode is presented by Victoria Derbyshire and Vitaly Shevchenko. The producers were Laurie Kalus and Ben Carter. The technical producers were Ben Andrews and Mike Regaard. The series producer is Tim Walklate. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Today, we look at talks between world leaders and their officials in Turkey, where a breakthrough on peace in Ukraine was hoped for.Ukrainian President Volodymyr Zelensky met with Turkish leader Recep Tayyip Erdoğan in the country's capital Ankara, but Russian President Vladimir Putin stayed away despite having proposed talks.Russia editor Steve Rosenberg joins to discuss what Putin's thinking is, as does former MI6 officer Christopher Steele.And - positive news for the UK's economy. It's grew more than expected at the start of the year. Deputy economics editor Dharshini David tells Adam whether it's expected to continue to grow.You can now listen to Newscast on a smart speaker. If you want to listen, just say "Ask BBC Sounds to play Newscast”. It works on most smart speakers. You can join our Newscast online community here: https://discord.gg/m3YPUGv9New episodes released every day. If you're in the UK, for more News and Current Affairs podcasts from the BBC, listen on BBC Sounds: https://bit.ly/3ENLcS1 Newscast brings you daily analysis of the latest political news stories from the BBC. It was presented by Adam Fleming. It was made by Chris Flynn with Shiler Mahmoudi, Julia Webster, and Rufus Gray. The technical producer was James Piper. The assistant editor is Chris Gray. The editor is Sam Bonham.

In this exciting episode, Shawn sits down with Joni Wolfswinkel, alongside industry leaders Josh Huite and Steve Rosenberg, to announce a game-changing event for entrepreneurs in Houston: the Strategic Growth Accelerator! Mark your calendars for August 22, 2025, because this one-day power-packed event at Hochzeit Hall in Old Town Spring is designed to equip you with the tools, strategies, and mindset needed to elevate your business to new heights. Join us as Joni shares her expert insights on building and managing an international workforce—discover how hiring global talent can reduce costs while fueling innovation and growth. Meanwhile, Shawn, Josh, and Steve delve into what makes this event so unique: from scaling your business with proven strategies to becoming the leader your team needs. Steve Rozenberg offers his secrets to smart, effective scaling, while Josh Huite reveals how to unlock your leadership potential and inspire your team to succeed. With a wealth of experience combined, Joni, Josh, and Steve are set to share their invaluable wisdom, strategies, and practical tips that can help entrepreneurs elevate their businesses to the next level. Listeners will discover why this event is a must-attend, featuring engaging discussions that cover everything from innovative business strategies to personal growth and resilience in the competitive entrepreneurial landscape. Each speaker brings their unique perspective and expertise, providing attendees with actionable takeaways they can implement right away. This episode is a must-listen for entrepreneurs eager to accelerate their growth and gain actionable wisdom from industry veterans. Whether you're just starting out or looking to break through to the next level, the Strategic Growth Accelerator promises practical insights that can transform your business trajectory. Don't miss out on this exclusive opportunity! Early bird registration is just $297 if you sign up by May 31st—space is limited, so reserve your spot today. The Strategic Growth Accelerator Event Website Link: https://www.wolfdenevents.com/ The Strategic Growth Accelerator Event Invitation Link: https://www.eventbrite.com/e/strategic-growth-accelerator-tickets-1303026911569?aff=oddtdtcreator The Strategic Growth Accelerator Event Sponsorship Link: https://www.eventbrite.com/e/1304634088679?aff=oddtdtcreator The Strategic Growth Accelerator Happy Hour Link: https://www.eventbrite.com/e/1304625412729?aff=oddtdtcreator

After Vladimir Putin's limited ‘Easter truce' ended, we're joined by the BBC's Russia editor, Steve Rosenberg, to discuss whether the Kremlin is serious about bilateral negotiations with Ukraine. And we talk to Alexander Vindman - the former US National Security Council official, who was a star witness in Donald Trump's first impeachment inquiry. He has a lot to say about US policy on Ukraine and what the future could look like if Washington pulls out of peace talks. Today's episode is presented by Victoria Derbyshire and Vitaly Shevchenko. The producers were Laurie Kalus and Ben Carter. The technical producer was Jonny Hall. The editor is Max Deveson. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on our Discord server here: tinyurl.com/ukrainecastdiscord

Join Ericka Redic and Steve Rosenberg as they welcome Director of Education and Community Engagement at the Jewish Institute for Liberal Values (JILV), Dr. Brandy Shufutinsky. Together, they discuss how wokeism and antisemitism have infiltrated America's education system and what we can do to fight back. Brash, irreverent, and mostly peaceful! Stay in contact with […]

Steve Rosenberg, Russia Editor for BBC News, is in Moscow on the third anniversary of Russia's full-scale invasion of Ukraine.

What have Russians won and lost during the conflict in Ukraine? Three years after the start of its full-scale invasion, Russia has entered talks with Donald Trump – and not Kyiv – about ending the war. For Vladimir Putin, this could be a chance to end the conflict on his terms, and forge a new international order with Russia and the US at its centre. But what about the people who live under Putin's rule? What do Russians stand to gain from these talks? On this episode, presenter Lucy Hockings is joined by the BBC's Russia editor Steve Rosenberg.The Global Story brings you trusted insights from BBC journalists worldwide. We want your ideas, stories and experiences to help us understand and tell #TheGlobalStory. Email us at theglobalstory@bbc.com You can also message us or leave a voice note via Whatsapp on +44 330 123 9480.Producers: Peter Goffin and Mhairi MacKenzieSound engineer: Mike RegaardAssistant editor: Sergi Forcada FreixasSenior news editor: China Collins

Today, we look at President Donald Trump's claim that there's a “good possibility” that the Ukraine war could be about to end.He spoke to Russian President Putin and Ukrainian President Volodymyr Zelensky during separate phone calls. Chief international correspondent Lyse Doucet and Russia editor Steve Rosenberg talk through what we know.Chris is on to talk about stories regarding the Chancellor Rachel Reeves's CV, and her expenses when she was working for a bank in a previous job.And, the CEO of BBC News Deborah Turness is warning about the “threat” AI poses to people using it to access news.You can now listen to Newscast on a smart speaker. If you want to listen, just say "Ask BBC Sounds to play Newscast”. It works on most smart speakers.You can join our Newscast online community here: https://tinyurl.com/newscastcommunityhereNewscast brings you daily analysis of the latest political news stories from the BBC. It was presented by Adam Fleming. It was made by Chris Flynn with Shiler Mahmoudi. The technical producer was Ben Andrews. The assistant editor is Chris Gray. The editor is Sam Bonham.

In this episode, Dr. Alexandria Wise speaks with Steve Rosenberg, CEO of uMotif, recorded from the CNS Summit 2024 exhibit floor. With over four decades of experience in software development and two decades in clinical research, Steve shares his journey from early tech innovations to his current mission of revolutionizing patient engagement and site support in clinical trials.Steve discusses the pivotal role of patient-centric tools in modernizing clinical research, emphasizing the need to recognize and support patients as key contributors to advancements in medicine. He also delves into the growing challenges faced by clinical sites, the potential of AI and computer modeling to streamline trials, and his vision for a future where the industry prioritizes patient and site experiences over protocol complexity.The views expressed in this podcast belong solely to the speakers and do not represent those of their organization. If you want access to more future-focused, actionable insights to help biopharmaceutical companies better execute and succeed in a constantly evolving environment, visit the Syneos Health Insights Hub. The perspectives you'll find there are driven by dynamic research and crafted by subject matter experts focused on real answers to help guide decision-making and investment. You can find it all at insightshub.health. Like what you're hearing? Be sure to rate and review us! We want to hear from you! If there's a topic you'd like us to cover on a future episode, contact us at podcast@syneoshealth.com.

After listener Margaret got in touch asking about Steve Rosenberg's life in Moscow as the BBC's Russia Editor, Nick and Amol sat down with him to find out how the country has changed over the years that he has lived there and what it's like reporting from Russia now.They talk about the challenges he faces, how he reports impartially and accurately on Vladimir Putin, how he relaxes and what it was like playing the piano for Mikhail Gorbachev.To get Amol and Nick's take on the biggest stories and insights from behind the scenes at the UK's most influential radio news programme make sure you hit subscribe on BBC Sounds. That way you'll get an alert every time we release a new episode, and you won't miss our extra bonus episodes either. GET IN TOUCH: * Send us a message or a voice note via WhatsApp to +44 330 123 4346 * Email today@bbc.co.uk The Today Podcast is hosted by Amol Rajan and Nick Robinson who are both presenters of BBC Radio 4's Today programme. Amol was the BBC's media editor for six years and is the former editor of the Independent, he's also the current presenter of University Challenge. Nick has presented the Today programme since 2015, he was the BBC's political editor for ten years before that and also previously worked as ITV's political editor. This episode was made by Lewis Vickers with Nadia Gyane and Grace Reeve. Digital production was by Nadia Gyane. The technical producer was Jonny Baker. The editor is Louisa Lewis. The executive producer is Owenna Griffiths.

Morse code transcription: vvv vvv Stephen Fry treats his chronic pain as a friend The uplifting science stories that turned heads in 2024 Hawaii volcano Warning after toddler nearly runs off cliff Blackburn Third murder arrest after Christmas Day pub row death Three migrants die attempting English Channel crossing On the fifth day of Christmas Norfolks five gold rings Who died in 2024 Notable deaths of the year Putin reaches 25 years in charge of Russia, but has he taken care of country, asks Steve Rosenberg Thousands protest in Georgia ahead of political showdown Manchester Airport train services hit by 100k cable theft

Morse code transcription: vvv vvv Three migrants die attempting English Channel crossing Putin reaches 25 years in charge of Russia, but has he taken care of country, asks Steve Rosenberg Manchester Airport train services hit by 100k cable theft Thousands protest in Georgia ahead of political showdown Stephen Fry treats his chronic pain as a friend Hawaii volcano Warning after toddler nearly runs off cliff The uplifting science stories that turned heads in 2024 Blackburn Third murder arrest after Christmas Day pub row death Who died in 2024 Notable deaths of the year On the fifth day of Christmas Norfolks five gold rings

Morse code transcription: vvv vvv Who died in 2024 Notable deaths of the year Blackburn Third murder arrest after Christmas Day pub row death The uplifting science stories that turned heads in 2024 Thousands protest in Georgia ahead of political showdown Putin reaches 25 years in charge of Russia, but has he taken care of country, asks Steve Rosenberg Stephen Fry treats his chronic pain as a friend Manchester Airport train services hit by 100k cable theft Hawaii volcano Warning after toddler nearly runs off cliff Three migrants die attempting English Channel crossing On the fifth day of Christmas Norfolks five gold rings

Morse code transcription: vvv vvv The uplifting science stories that turned heads in 2024 Who died in 2024 Notable deaths of the year Putin reaches 25 years in charge of Russia, but has he taken care of country, asks Steve Rosenberg Blackburn Third murder arrest after Christmas Day pub row death Hawaii volcano Warning after toddler nearly runs off cliff On the fifth day of Christmas Norfolks five gold rings Manchester Airport train services hit by 100k cable theft Stephen Fry treats his chronic pain as a friend Thousands protest in Georgia ahead of political showdown Three migrants die attempting English Channel crossing

Kate Adie presents stories from Russia, Mayotte, Liechtenstein and France.BBC Russia editor Steve Rosenberg is regarded as a 'propagandist' by some Russians, but a song he wrote about a Russian friend seemed to thaw the ice, and unexpectedly struck a chord with fellow Muscovites.France held a day of national mourning this week in tribute to those who died after Cyclone Chido devasted the Indian Ocean territory of Mayotte earlier this month, bringing winds of up to 160 miles per hour. Mayotte was already France's most impoverished territory, but the storm, which was the worst to hit the archipelago in 90 years, flattened areas where many people live in shacks, leaving behind fields of dirt and debris. Mayeni Jones describes the challenges of trying to reach the island when she was deployed there.Liechtenstein lays claim to being one of the worst football teams in the world. It was recently on a 40-game losing streak, until it recently faced Hong Kong on its home turf. Jacob Panons - a loyal supporter of the Hong Kong team - witnessed the stand-off between the two minnows.Thanks to his Christmas stories, Charles Dickens is often associated with this time of year. But our Paris correspondent, Hugh Schofield, has come to discover more about another passion in the Victorian novelist's life – his love of France.Series Producer: Serena Tarling Production Coordinators: Katie Morrison & Sophie Hill Editor: Richard Fenton-Smith

Today, we look at what the end of Bashar al-Assad's regime means for Syria. As huge crowds gather at a notorious Damascus prison looking for prisoners held under the Assad regime Adam speaks to Lina Sinjab, the BBC's Middle East Correspondent. He is also joined by chief Jihadist media specialist for BBC monitoring, Mina Al-Lami, who profiles the rebel group's leader and legacy. And, the Kremlin say Bashar Al-Assad has been given asylum in Moscow after fleeing from Syria. Adam speaks to Russia editor Steve Rosenberg about how the fall of the Russian-supported regime is a blow to the country's prestige. You can now listen to Newscast on a smart speaker. If you want to listen, just say "Ask BBC Sounds to play Newscast”. It works on most smart speakers. You can join our Newscast online community here: https://tinyurl.com/newscastcommunityhere Newscast brings you daily analysis of the latest political news stories from the BBC. It was presented by Adam Fleming. It was made by Jack Maclaren with Anna Harris and Maddie Drury. The technical producer was Philip Bull. The assistant editor is Chris Gray. The editor is Sam Bonham.

Donald Trump has won the US election and will make a historic return to the White House. He's said he'd end the war in 24 hours but…..can he? We hear from Ukraine correspondent James Waterhouse in Kyiv, Russia editor Steve Rosenberg in Sochi and Victoria in Washington DC. They discuss what Trump's re-election actually mean for Ukraine.Today's episode is presented by Lucy Hockings and Vitaly Shevchenko. The producers were Arsenii Sokolov and Ben Carter. The technical producer was Hannah Montgomery. The series producer is Tim Walklate. The senior news editor is Sarah Wadeson. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Israel claims a bunker under a Beirut hospital holds hundreds of millions of dollars belonging to Hezbollah. The hospital has been evacuated Brazil,Russia,India,China and South Africa, also know as BRICS, are set to have a summit meeting this week. The BBC's Steve Rosenberg tells us more And the worlds largest entertainment company Disney, has announced its CEO's successor will be announced in 2026

Russia has revealed it will boost its defence spending by a quarter to $145 billion in 2025. But is Putin's war economy sustainable? What does all this mean for life in the country? And how could it impact the war?The BBC's Steve Rosenberg joins us from a Moscow supermarket, Russian citizen ‘Gleb' explains why there are dozens of types of cola in shops, and Bloomberg's Stephanie Baker joins Carnegie's Alexander Gabuev to discuss whether Russians are feeling the pinch.Today's episode is presented by Victoria Derbyshire and Vitaly Shevchenko. The producers were Arsenii Sokolov, Cordelia Hemming and Ivana Davidovic. The technical producer was Ben Andrews. The series producer is Tim Walklate. The senior news editor is Sarah Wadeson. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Ever since the Kremlin's full-scale invasion of Ukraine there have been widespread reports of Russians reporting fellow citizens to the police for anti-war views; often leading to prosecution and, in some cases, prison sentences. It's revived memories of the Soviet past when informing on colleagues and neighbours was actively encouraged. Katya Adler speaks to our Russia editor Steve Rosenberg about the people he has met who have been caught up in this new wave of denunciations.The Global Story brings you trusted insights from BBC journalists worldwide. We want your ideas, stories and experiences to help us understand and tell #TheGlobalStory. Email us at theglobalstory@bbc.com You can also message us or leave a voice note via WhatsApp on +44 330 123 9480.Producers: Alice Aylett Roberts, Eleanor Sly and Beth Timmins.Sound Engineers: Antonio Fernandes and Rohan Madison.Assistant Editor: Sergi Forcada Freixas.Senior News Editor: Richard Fenton-Smith.

Pavel Durov, the CEO of messaging app Telegram, has been arrested in France. For an executive of a big social media company to face a criminal enquiry is highly unusual. Mike Isaac, Tech Correspondent of The New York Times and Steve Rosenberg, Russia Editor for BBC News discuss the case. The Onion, the satirical news website, is relaunching a print edition. Its editor, Chad Nackers, explains the appeal of a traditional newspaper. A Chinese produced video game, Black Myth: Wukong, has become one of the most successful launches ever. Keza McDonald, Games Editor at The Guardian and Frankie Ward, e-sports host and broadcaster discuss this - and other gaming news. Presenter: Ros Atkins Producer: Simon Richardson Assistant Producer: Lucy Wai

This week, Robert Chernin and Ericka Redic are joined by Steve Rosenberg, Principal of the GSD Group, author of MAKE BOLD THINGS HAPPEN: Inspirational Stories from Sports, Business, and Life, and pro-Israel advocate. In this episode, Robert, Ericka, and Steve discuss Israel Appreciation Day 2024, his work with various NGOs in Israel and the United […]

After the detention in France of Pavel Durov, owner of the controversial Telegram app, we explore what the first arrest of a social media boss means for content regulation and freedom of speech. As a new parliamentary term begins, we find out how the new Labour government is managing the media. Also in the programme, there's a new Chinese computer game which is breaking records – and revealing details of how the gaming industry is evolving. Plus, satirical outlet The Onion is returning to print. We find out why.Guests: Mike Isaac, Tech Correspondent, The New York Times; Steve Rosenberg, Russia Editor, BBC News; Matt Chorley, Presenter, BBC Radio 5 Live; Eleanor Langford, Political Reporter, The i; Keza MacDonald, Games Editor, The Guardian; Frankie Ward, eSports broadcaster; Chad Nackers, Editor, The Onion Presenter: Ros Atkins Producer: Simon Richardson Assistant Producer: Lucy Wai

In this conversation, Bob Turner interviews Steve Rosenberg, a successful entrepreneur and coach. Steve shares his journey from being an airline pilot to building a real estate management company and eventually becoming a business coach. He emphasizes the importance of having a solid foundation and systems in place to run a successful business. Steve also discusses the three key aspects of a vital business: monetization, systemization, and duplication. He encourages entrepreneurs to prioritize their health and fitness and create time for self-improvement. In this conversation, Steve Rozenberg shares his personal experience with adversity and loss, specifically the tragic death of his son. He emphasizes the importance of cherishing and creating memories with loved ones, as time is limited. Steve also discusses the significance of giving back and helping others, which led him to establish a nonprofit scholarship foundation in honor of his son. He highlights the value of being transparent, vulnerable, and approachable in leadership roles. Steve's edge is his ability to slow things down and methodically approach challenges, drawing from his training as an airline pilot. He encourages entrepreneurs to embrace failure and remember their initial dreams and motivations. Connect with Steve at: www.Steverozenberg.com @rozenbergsteve (Instagram)

Kate Adie presents stories from Russia, Nigeria, the US, Ecuador and Italy.Ukraine's surprise attack on Russia's western border region of Kursk caused authorities to declare a state of emergency there. The incursion is now in its second week and is the deepest into Russian territory since Vladimir Putin launched his invasion. Steve Rosenberg has been watching the reaction in Moscow and reflects on another major news event soon after he first arrived in Russia.Nigeria has been in the throes of an economic crisis which earlier this month led to 10 days of protests across the country. More than 700 demonstrators were arrested, 22 were killed and many more were injured. The marches eventually petered out but the causes of their discontent, though, don't look likely to go away. Simi Jolaoso has been to an open-air market in Lagos.In certain US states, parents are offered school vouchers as a means of paying for their children to go to private school, should they so choose, using public funding which would otherwise be used for state-funded school places. The vouchers scheme has polarised communities across the state of Arizona, says Mark Moran in Queen Creek.In Ecuador, President Daniel Noboa has moved to clampdown on organised crime and the drug cartels since he took power, amid a surge in outbreaks of violence. Danny Wiser was in Guayaquil, which has seen the worst of the violence and learned how it's impacting key areas of daily life.The Italian city of Trieste has a complex identity, thanks to its history and its geography. It was once part of the Austro-Hungarian empire. Sara Wheeler found out more about its past on a visit this Summer.Series Producer: Serena Tarling Editor: Tom Bigwood Production Coordinators: Sophie Hill & Katie Morrison

Today, we look at the latest inflation figures and how Russian state media are covering Ukraine's continuing advance into Russia.James Cook is in for Adam, and he's joined by political correspondent Alex Forsyth and chief economic correspondent Dharshini David to discuss the rise in the rate of UK inflation. They also talk about the Scottish government's spending cuts, which include no longer providing winter fuel payments to all pensioners.And Russia editor Steve Rosenberg speaks to James from Moscow about Ukraine's advancements into Russia. You can join our Newscast online community here: https://tinyurl.com/newscastcommunityhereYou can now listen to Newscast on a smart speaker. If you want to listen, just say "Ask BBC Sounds to play Newscast”. It works on most smart speakers.Newscast brings you daily analysis of the latest political news stories from the BBC. It was presented by James Cook. It was made by Chris Flynn with Miranda Slade, Gemma Roper and Kris Jalowiecki. The technical producer was Michael Regaard. The assistant editor is Chris Gray. The senior news editor is Sam Bonham.

Steve Rosenberg, Russia Editor for BBC News, discusses the reaction in Moscow to the ncursion by Ukranian troops, the first time in 80-years foreign troops are fighting on Russian soil.

How has the shock cross-border offensive gone down in Russia?We hear from Nikita, whose family and friends live in Kursk, about what they've been witnessing and how worried they are.BBC Russia editor, Steve Rosenberg, tells us how this is going down in the Kremlin and what President Putin might down nextAnd Olga Robinson from BBC Verify is in the studio to help us understand the picture more clearly. Today's episode is presented by Jamie Coomarasamy and Vitaly Shevchenko. The producers were Arsenii Sokolov, Cordelia Hemming, Ivana Davidovic and Hatty Nash. The technical producer was Jonny Hall. The series producer is Tim Walklate. The senior news editor is Richard Fenton-Smith. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Today, now that the election dust has settled, what challenges do the new Labour government face in their first few days? One issue that is already demanding Labour's attention is the Tata Steelworks in Port Talbot in South Wales, with thousands of jobs currently at risk. And, the Conservatives are in search of a new leader. Potential contenders, Victoria Atkins and Robert Jenrick spoke to Laura this morning. Are they putting their names in the hat? And who is being touted as a potential caretaker leader?Plus, Henry channels his inner Steve Rosenberg by sharing his ability on the piano! You can join our Newscast online community here: https://tinyurl.com/newscastcommunityhere Newscast brings you daily analysis of the latest political news stories from the BBC. It was presented by Adam Fleming. It was made by Jack Maclaren with Josh Jenkins. The technical producer was Riccardo McCarthy . The assistant editor is Chris Gray. The editor is Sam Bonham.

Kate Adie presents stories from Russia, The Netherlands, Taiwan, Vanuatu and Germany.The trial of US journalist, Evan Gershkovich in the city of Yekaterinburg will be conducted behind closed doors. He is just one of many journalists who went to Russia to report on the country, as Vladimir Putin's clampdown on media freedoms intensified. Steve Rosenberg was in Yekaterinburg and reflects on Russia's handling of the case.Last year, just over 9000 deaths - around 5% of the total number - occurred as a result of euthanasia in the Netherlands, where it's legal. It's very rare, but every year, there are more Dutch couples choosing to end their lives at the same time. Linda Pressly met someone whose parents made the decision to die together.In Taiwan, civil liberties are strongly supported, and it is now one of the world's most progressive countries regarding gay rights. On a recent visit to the capital Taipei, Lucy Ash meets some who fear that should China invade in the future, hard-won rights could be taken away.In the South Pacific, Vanuatu is grappling with what happens when a significant proportion of its workforce is lured away by higher paid jobs in hospitality, agriculture and elderly care to the likes of New Zealand and Australia. In Port Vila, Rebecca Root speaks to locals about what that means for a country struggling to build up its own economy.And finally, the UEFA Euro 2024 football championship is taking place at a time when Europe is seeing many political rifts. On a tour of some of the host cities in Germany, James Helm reflects on how football tournaments still have the power to unite rather than divide.Series Producer: Serena Tarling Editor: Richard Vadon and Tom Bigwood Production Coordinator: Katie Morrison

On Wednesday, Evan Gershkovich, the Wall Street Journal reporter arrested in Russia last year goes on trial. Russian officials have accused the Wall Street Journal reporter of collecting "secret information" from a Russian tank factory for the CIA. An allegation he denies. The BBC's Steve Rosenberg is in the city of Yekaterinburg where the trial is taking place. And we also hear from Evan's friend Polina Ivanova, and his boss at the Wall Street Journal, Deborah Ball.Today's episode is presented by Vitaly Shevchenko. Produced by Clare Williamson with Josh Jenkins, Bella Saltiel and Sanjana Idnani. The technical producer was Rohan Madison. The series producer is Tim Walklate. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

In this episode of the Blue Gems podcast, the focus is on building successful businesses with Steve Rosenberg. Steve shares three crucial aspects for business success, the importance of leadership, creating systems over people-focused operations, and maintaining a forward-thinking mindset to ensure business growth and sustainability. Top takeaways from this episode include: 1) Focus on the Essentials of Business: Emphasize monetization (sales and marketing), systemization (creating efficient systems), and duplication (training and scaling with a capable team). 2) Mindset and Leadership: Successful businesses start with the right mindset and strong leadership. Leaders must inspire and create a vision that their team can rally behind while also holding themselves accountable. 3) Importance of Creating Memories: Beyond financial success, building a business should provide the freedom to create meaningful memories with loved ones, as these moments are invaluable and irreplaceable. Follow Steve online: https://www.instagram.com/rozenbergsteve/ Let's connect! ► Blue Gems Instagram: https://www.instagram.com/bluegemsgroup/   ► JB's Instagram: https://www.instagram.com/jbinvested/ ► Aidan's Instagram: https://www.instagram.com/aidangroll/ ► Blue Gems STR Management: https://bluegemsmgmt.co ► STR Meetup: https://bluegemsgroup.com Timestamps: 00:00 - Intro 02:32 - Steve's Background: Upbringing and motivation. 07:26 - Lessons from property management. 08:12 - Transitioning from investor to business owner. 23:41 - Key components for business success. 36:18 - Generating consistent business growth. 48:00 - Continual growth and self-improvement. 52:30 - Navigating Business Partnerships: Clear communication and roles. 57:05 - Developing a success-oriented mindset. 59:00 - Importance of being a lifelong learner. *None of this is meant to be specific investment advice, it's for entertainment purposes only.

The most enthralling conversation I've ever had with anyone on cancer. It's with Charlie Swanton who is a senior group leader at the Francis Crick Institute, the Royal Society Napier Professor in Cancer and medical oncologist at University College London, co-director of Cancer Research UK.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with audio links and many external linksEric Topol (00:07):Well, hello, this is Eric Topol with Ground Truths, and I am really fortunate today to connect us with Charlie Swanton, who is if not the most prolific researcher in the space of oncology and medicine, and he's right up there. Charlie is a physician scientist who is an oncologist at Francis Crick and he heads up the lung cancer area there. So Charlie, welcome.Charles Swanton (00:40):Thank you, Eric. Nice to meet you.Learning from a FailureEric Topol (00:43):Well, it really is a treat because I've been reading your papers and they're diverse. They're not just on cancer. Could be connecting things like air pollution, it could be Covid, it could be AI, all sorts of things. And it's really quite extraordinary. So I thought I'd start out with a really interesting short paper you wrote towards the end of last year to give a sense about you. It was called Turning a failing PhD around. And that's good because it's kind of historical anchoring. Before we get into some of your latest contributions, maybe can you tell us about that story about what you went through with your PhD?Charles Swanton (01:26):Yeah, well thank you, Eric. I got into research quite early. I did what you in the US would call the MD PhD program. So in my twenties I started a PhD in a molecular biology lab at what was then called the Imperial Cancer Research Fund, which was the sort of the mecca for DNA tumor viruses, if you like. It was really the place to go if you wanted to study how DNA tumor viruses worked, and many of the components of the cell cycle were discovered there in the 80s and 90s. Of course, Paul Nurse was the director of the institute at the time who discovered cdc2, the archetypal regulator of the cell cycle that led to his Nobel Prize. So it was a very exciting place to work, but my PhD wasn't going terribly well. And sort of 18, 19 months into my PhD, I was summoned for my midterm reports and it was not materializing rapidly enough.(02:25):And I sat down with my graduate student supervisors who were very kind, very generous, but basically said, Charlie, this isn't going well, is it? You've got two choices. You can either go back to medical school or change PhD projects. What do you want to do? And I said, well, I can't go back to medical school because I'm now two years behind. So instead I think what I'll do is I'll change PhD projects. And they asked me what I'd like to do. And back then we didn't know how p21, the CDK inhibitor bound to cyclin D, and I said, that's what I want to understand how these proteins interact biochemically. And they said, how are you going to do that? And I said, I'm not too sure, but maybe we'll try yeast two-hybrid screen and a mutagenesis screen. And that didn't work either. And in the end, something remarkable happened.(03:14):My PhD boss, Nic Jones, who's a great guy, still is, retired though now, but a phenomenal scientist. He put me in touch with a colleague who actually works next door to me now at the Francis Crick Institute called Neil McDonald, a structural biologist. And they had just solved, well, the community had just solved the structure. Pavletich just solved the structure of cyclin A CDK2. And so, Neil could show me this beautiful image of the crystal structure in 3D of cyclin A, and we could mirror cyclin D onto it and find the surface residue. So I spent the whole of my summer holiday mutating every surface exposed acid on cyclin D to an alanine until I found one that failed to interact with p21, but could still bind the CDK. And that little breakthrough, very little breakthrough led to this discovery that I had where the viral cyclins encoded by Kaposi sarcoma herpes virus, very similar to cyclin D, except in this one region that I had found interactive with a CDK inhibitor protein p21.(04:17):And so, I asked my boss, what do you think about the possibility this cyclin could have evolved from cyclin D but now mutated its surface residues in a specific area so that it can't be inhibited by any of the control proteins in the mammalian cell cycle? He said, it's a great idea, Charlie, give it a shot. And it worked. And then six months later, we got a Nature paper. And that for me was like, I cannot tell you how exciting, not the Nature paper so much as the discovery that you were the first person in the world to ever see this beautiful aspect of evolutionary biology at play and how this cyclin had adapted to just drive the cell cycle without being inhibited. For me, just, I mean, it was like a dream come true, and I never experienced anything like it before, and I guess it's sizes the equivalent to me of a class A drug. You get such a buzz out of it and over the years you sort of long for that to happen again. And occasionally it does, and it's just a wonderful profession.Eric Topol (05:20):Well, I thought that it was such a great story because here you were about to fail. I mean literally fail, and you really were able to turn it around and it should give hope to everybody working in science out there that they could just be right around the corner from a significant discovery.Charles Swanton (05:36):I think what doesn't break you makes you stronger. You just got to plow on if you love it enough, you'll find a way forward eventually, I hope.Tracing the Evolution of Cancer (TRACERx)Eric Topol (05:44):Yeah, no question about that. Now, some of your recent contributions, I mean, it's just amazing to me. I just try to keep up with the literature just keeping up with you.Charles Swanton (05:58):Eric, it's sweet of you. The first thing to say is it's not just me. This is a big community of lung cancer researchers we have thanks to Cancer Research UK funded around TRACERx and the lung cancer center. Every one of my papers has three corresponding authors, multiple co-first authors that all contribute in this multidisciplinary team to the sort of series of small incremental discoveries. And it's absolutely not just me. I've got an amazing team of scientists who I work with and learn from, so it's sweet to give me the credit.Eric Topol (06:30):I think what you're saying is really important. It is a team, but I think what I see through it all is that you're an inspiration to the team. You pull people together from all over the world on these projects and it's pretty extraordinary, so that's what I would say.Charles Swanton (06:49):The lung community, Eric, the lung cancer community is just unbelievably conducive to collaboration and advancing understanding of the disease together. It's just such a privilege to be working in this field. I know that sounds terribly corny, but it is true. I don't think I recall a single email to anybody where I've asked if we can collaborate where they've said, no, everybody wants to help. Everybody wants to work together on this challenge. It's just such an amazing field to be working in.Eric Topol (07:19):Yeah. Well I was going to ask you about that. And of course you could have restricted your efforts or focused on different cancers. What made you land in lung cancer? Not that that's only part of what you're working on, but that being the main thing, what drew you to that area?Charles Swanton (07:39):So I think the answer to your question is back in 2008 when I was looking for a niche, back then it was lung cancer was just on the brink of becoming an exciting place to work, but back then nobody wanted to work in that field. So there was a chair position in thoracic oncology and precision medicine open at University College London Hospital that had been open, as I understand it for two years. And I don't think anybody had applied. So I applied and because I was the only one, I got it and the rest is history.(08:16):And of course that was right at the time when the IPASS draft from Tony Mok was published and was just a bit after when the poster child of EGFR TKIs and EGFR mutant lung cancer had finally proven that if you segregate that population of patients with EGFR activating mutation, they do incredibly well on an EGFR inhibitor. And that was sort of the solid tumor poster child along with Herceptin of precision medicine, I think. And you saw the data at ASCO this week of Lorlatinib in re-arranged lung cancer. Patients are living way beyond five years now, and people are actually talking about this disease being more like CML. I mean, it's extraordinary the progress that's been made in the last two decades in my short career.Eric Topol (09:02):Actually, I do want to have you put that in perspective because it's really important what you just mentioned. I was going to ask you about this ASCO study with the AKT subgroup. So the cancer landscape of the lung has changed so much from what used to be a disease of cigarette smoking to now one of, I guess adenocarcinoma, non-small cell carcinoma, not related to cigarettes. We're going to talk about air pollution in a minute. This group that had, as you say, 60 month, five year plus survival versus what the standard therapy was a year plus is so extraordinary. But is that just a small subgroup within small cell lung cancer?Charles Swanton (09:48):Yes, it is, unfortunately. It's just a small subgroup. In our practice, probably less than 1% of all presentations often in never smokers, often in female, never smokers. So it is still in the UK at least a minority subset of adenocarcinomas, but it's still, as you rightly say, a minority of patients that we can make a big difference to with a drug that's pretty well tolerated, crosses the blood-brain barrier and prevents central nervous system relapse and progression. It really is an extraordinary breakthrough, I think. But that said, we're also seeing advances in smoking associated lung cancer with a high mutational burden with checkpoint inhibitor therapy, particularly in the neoadjuvant setting now prior to surgery. That's really, really impressive indeed. And adjuvant checkpoint inhibitor therapies as well as in the metastatic setting are absolutely improving survival times and outcomes now in a way that we couldn't have dreamt of 15 years ago. We've got much more than just platinum-based chemo is basically the bottom line now.Revving Up ImmunotherapyEric Topol (10:56):Right, right. Well that actually gets a natural question about immunotherapy also is one of the moving parts actually just amazing to me how that's really, it's almost like we're just scratching the surface of immunotherapy now with checkpoint inhibitors because the more we get the immune system revved up, the more we're seeing results, whether it's with vaccines or CAR-T, I mean it seems like we're just at the early stages of getting the immune system where it needs to be to tackle the cancer. What's your thought about that?Charles Swanton (11:32):I think you're absolutely right. We are, we're at the beginning of a very long journey thanks to Jim Allison and Honjo. We've got CTLA4 and PD-1/PDL-1 axis to target that's made a dramatic difference across multiple solid tumor types including melanoma and lung cancer. But undoubtedly, there are other targets we've seen LAG-3 and melanoma and then we're seeing new ways, as you rightly put it to mobilize the immune system to target cancers. And that can be done through vaccine based approaches where you stimulate the immune system against the patient's specific mutations in their cancer or adoptive T-cell therapies where you take the T-cells out of the tumor, you prime them against the mutations found in the tumor, you expand them and then give them back to the patient. And colleagues in the US, Steve Rosenberg and John Haanen in the Netherlands have done a remarkable job there in the context of melanoma, we're not a million miles away from European approvals and academic initiated manufacturing of T-cells for patients in national health systems like in the Netherlands.(12:50):John Haanen's work is remarkable in that regard. And then there are really spectacular ways of altering T-cells to be able to either migrate to the tumor or to target specific tumor antigens. You mentioned CAR-T cell therapies in the context of acute leukemia, really extraordinary developments there. And myeloma and diffuse large B-cell lymphoma as well as even in solid tumors are showing efficacy. And I really am very excited about the future of what we call biological therapies, be it vaccines, an antibody drug conjugates and T-cell therapies. I think cancer is a constantly adapting evolutionary force to be reckoned with what better system to combat it than our evolving immune system. It strikes me as being a future solution to many of these refractory cancers we still find difficult to treat.Eric Topol (13:48):Yeah, your point is an interesting parallel how the SARS-CoV-2 virus is constantly mutating and becoming more evasive as is the tumor in a person and the fact that we can try to amp up the immune system with these various means that you just were reviewing. You mentioned the other category that's very hot right now, which is the antibody drug conjugates. Could you explain a bit about how they work and why you think this is an important part of the future for cancer?Antibody-Drug ConjugatesCharles Swanton (14:26):That's a great question. So one of the challenges with chemotherapy, as you know, is the normal tissue toxicity. So for instance, neutropenia, hair loss, bowel dysfunction, diarrhea, epithelial damage, essentially as you know, cytotoxics affect rapidly dividing tissues, so bone marrow, epithelial tissues. And because until relatively recently we had no way of targeting chemotherapy patients experienced side effects associated with them. So over the last decade or so, pioneers in this field have brought together this idea of biological therapies linked with chemotherapy through a biological linker. And so one poster chart of that would be the drug T-DXd, which is essentially Herceptin linked to a chemotherapy drug. And this is just the most extraordinary drug that obviously binds the HER2 receptor, but brings the chemotherapy and proximity of the tumor. The idea being the more drug you can get into the tumor and the less you're releasing into normal tissue, the more on tumor cytotoxicity you'll have and the less off tumor on target normal tissue side effects you'll have. And to a large extent, that's being shown to be the case. That doesn't mean they're completely toxicity free, they're not. And one of the side effects associated with these drugs is pneumonitis.(16:03):But that said, the efficacy is simply extraordinary. And for example, we're having to rewrite the rule books if you like, I think. I mean I'm not a breast cancer physician, I used to be a long time ago, but back in the past in the early 2000s, there was HER2 positive breast cancer and that's it. Now they're talking about HER2 low, HER2 ultra-low, all of which seem to in their own way be sensitive to T-DXd, albeit to a lower extent than HER2 positive disease. But the point is that there doesn't seem to be HER2 completely zero tumor group in breast cancer. And even the HER2-0 seem to benefit from T-DXd to an extent. And the question is why? And I think what people are thinking now is it's a combination of very low cell service expression of HER2 that's undetectable by conventional methods like immunohistochemistry, but also something exquisitely specific about the way in which HER2 is mobilized on the membrane and taken back into the cell. That seems to be specific to the breast cancer cell but not normal tissue. So in other words, the antibody drug conjugate binds the tumor cell, it's thought the whole receptor's internalized into the endosome, and that's where the toxicity then happens. And it's something to do with the endosomal trafficking with the low level expression and internalization of the receptor. That may well be the reason why these HER2 low tumors are so sensitive to this beautiful technology.Eric Topol (17:38):Now I mean it is an amazing technology in all these years where we just were basically indiscriminately trying to kill cells and hoping that the cancer would succumb. And now you're finding whether you want to call it a carry or vector or Trojan horse, whatever you want to call it, but do you see that analogy of the HER2 receptor that's going to be seen across the board in other cancers?Charles Swanton (18:02):That's the big question, Eric. I think, and have we just lucked out with T-DXd, will we find other T-DXd like ADCs targeting other proteins? I mean there are a lot of ADCs being developed against a lot of different cell surface proteins, and I think the jury's still out. I'm confident we will, but we have to bear in mind that biology is a fickle friend and there may be something here related to the internalization of the receptor in breast cancer that makes this disease so exquisitely sensitive. So I think we just don't know yet. I'm reasonably confident that we will find other targets that are as profoundly sensitive as HER2 positive breast cancer, but time will tell.Cancer, A Systemic DiseaseEric Topol (18:49):Right. Now along these lines, well the recent paper that you had in Cell, called embracing cancer complexity, which we've talking about a bit, in fact it's kind of those two words go together awfully well, but hallmarks of systemic disease, this was a masterful review, as you say with the team that you led. But can you tell us about what's your main perspective about this systemic disease? I mean obviously there's been the cancer is like cardiovascular and cancers like this or that, but here you really brought it together with systemic illness. What can you say about that?Charles Swanton (19:42):Well, thanks for the question first of all, Eric. So a lot of this comes from some of my medical experience of treating cancer and thinking to myself over the years, molecular biology has had a major footprint on advances in treating the disease undoubtedly. But there are still aspects of medicine where molecular biology has had very little impact, and often that is in areas of suffering in patients with advanced disease and cancer related to things like cancer cachexia, thrombophilia. What is the reason why patients die blood clots? What is the reason patients die of cancer at all? Even a simple question like that, we don't always know the answer to, on death certificates, we write metastatic disease as a cause of cancer death, but we have patients who die with often limited disease burden and no obvious proximal cause of death sometimes. And that's very perplexing, and we need to understand that process better.(20:41):And we need to understand aspects like cancer pain, for example, circadian rhythms affect biological sensitivity of cancer cells to drugs and what have you. Thinking about cancer rather than just sort of a single group of chaotically proliferating cells to a vision of cancer interacting both locally within a microenvironment but more distantly across organs and how organs communicate with the cancer through neuronal networks, for example, I think is going to be the next big challenge by setting the field over the next decade or two. And I think then thinking about more broadly what I mean by embracing complexity, I think some of that relates to the limitations of the model systems we use, trying to understand inter-organ crosstalk, some of the things you cover in your beautiful Twitter reviews. (←Ground Truths link) I remember recently you highlighted four publications that looked at central nervous system, immune cell crosstalk or central nervous system microbiome crosstalk. It's this sort of long range interaction between organs, between the central nervous system and the immune system and the cancer that I'm hugely interested in because I really think there are vital clues there that will unlock new targets that will enable us to control cancers more effectively if we just understood these complex networks better and had more sophisticated animal model systems to be able to interpret these interactions.Eric Topol (22:11):No, it's so important what you're bringing out, the mysteries that still we have to deal with cancer, why patients have all these issues or dying without really knowing what's happened no less, as you say, these new connects that are being discovered at a remarkable pace, as you mentioned, that ground truths. And also, for example, when I spoke with Michelle Monje, she's amazing on the cancer, where hijacking the brain cells and just pretty extraordinary things. Now that gets me to another line of work of yours. I mean there are many, but the issue of evolution of the tumor, and if you could put that in context, a hot area that's helping us elucidate these mechanisms is known as spatial omics or spatial biology. This whole idea of being able to get the spatial temporal progression through single cell sequencing and single cell nuclei, all the single cell omics. So if you could kind of take us through what have we learned with this technique and spatial omics that now has changed or illuminated our understanding of how cancer evolves?Charles Swanton (23:37):Yeah, great question. Well, I mean I think it helps us sort of rewind a bit and think about evolution in general. Genetic selection brought about by diverse environments and environmental pressures that force evolution, genetic evolution, and speciation down certain evolutionary roots. And I think one can think about cancers in a similar way. They start from a single cell and we can trace the evolutionary paths of cancers by single cell analysis as well as bulk sequencing of spatially separated tumor regions to be able to reconstruct their subclones. And that's taught us to some extent, what are the early events in tumor evolution? What are the biological mechanisms driving branched evolution? How does genome instability begin in tumors? And we found through TRACERx work, whole genome doubling is a major route through to driving chromosome instability along with mutagenic enzymes like APOBEC that drive both mutations and chromosomal instability.(24:44):And then that leads to a sort of adaptive radiation in a sense, not dissimilar to I guess the Cambrian explosion of evolutionary opportunity upon which natural selection can act. And that's when you start to see the hallmarks of immune evasion like loss of HLA, the immune recognition molecules that bind the neoantigens or even loss of the neoantigens altogether or mutation of beta 2 microglobulin that allow the tumor cells to now evolve below the radar, so to speak. But you allude to the sort of spatial technologies that allow us to start to interpret the microenvironments as well. And that then tells us what the evolutionary pressures are upon the tumor. And we're learning from those spatial technologies that these environments are incredibly diverse, actually interestingly seem to be converging on one important aspect I'd like to talk to you a little bit more about, which is the myeloid axis, which is these neutrophils, macrophages, et cetera, that seem to be associated with poor outcome and that will perhaps talk about pollution in a minute.(25:51):But I think they're creating a sort of chronic inflammatory response that allows these early nascent tumor cells to start to initiate into frankly tumor invasive cells and start to grow. And so, what we're seeing from these spatial technologies in lung cancer is that T-cells, predatory T-cells, force tumors to lose their HLA molecules and what have you to evade the immune system. But for reasons we don't understand, high neutrophil infiltration seems to be associated with poor outcome, poor metastasis free survival. And actually, those same neutrophils we've recently found actually even tracked to the metastasis sites of metastasis. So it's almost like this sort of symbiosis between the myeloid cells and the tumor cells in their biology and growth and progression of the tumor cells.Eric Topol (26:46):Yeah, I mean this white cell story, this seems to be getting legs and is relatively new, was this cracked because of the ability to do this type of work to in the past everything was, oh, it's cancer's heterogeneous and now we're getting pinpoint definition of what's going on.Charles Swanton (27:04):I think it's certainly contributed, but it's like everything in science, Eric, when you look back, there's evidence in the literature for pretty much everything we've ever discovered. You just need to put the pieces together. And I mean one example would be the neutrophil lymphocyte ratio in the blood as a hallmark of outcome in cancers and to checkpoint inhibitor blockade, maybe this begins to explain it, high neutrophils, immune suppressive environment, high neutrophils, high macrophages, high immune suppression, less benefit from checkpoint inhibitor therapy, whereas you want lymphocyte. So I think there are biomedical medical insights that help inform the biology we do in the lab that have been known for decades or more. And certainly the myeloid M2 axis in macrophages and what have you was known about way before these spatial technologies really came to fruition, I think.The Impact of Air PollutionEric Topol (28:01):Yeah. Well you touched on this about air pollution and that's another dimension of the work that you and your team have done. As you well know, there was a recent global burden of disease paper in the Lancet, which has now said that air pollution with particulate matter 2.5 less is the leading cause of the burden of disease in the world now.Charles Swanton (28:32):What did you think of that, Eric?Eric Topol (28:34):I mean, I was blown away. Totally blown away. And this is an era you've really worked on. So can you put it in perspective?Charles Swanton (28:42):Yeah. So we got into this because patients of mine, and many of my colleagues would ask the same question, I've never smoked doctor, I'm healthy. I'm in my mid 50s though they're often female and I've got lung cancer. Why is that doctor? I've had a good diet, I exercise, et cetera. And we didn't really have a very good answer for that, and I don't want to pretend for a minute we solved the whole problem. I think hopefully we've contributed to a little bit of understanding of why this may happen. But that aside, we knew that there were risk factors associated with lung cancer that included air pollution, radon exposure, of course, germline genetics, we mustn't forget very important germline variation. And I think there is evidence that all of them are associated with lung cancer risk in different ways. But we wanted to look at air pollution, particularly because there was an awful lot of evidence, several meta-analysis of over half a million individuals showing very convincingly with highly significant results that increasing PM 2.5 micron particulate levels were associated with increased risk of lung cancer.(29:59):To put that into perspective, where you are on the west coast of the US, it's relatively unpolluted. You would be talking about maybe five micrograms per meter cubed of PM2.5 in a place like San Diego or Western California, assuming there aren't any forest fires of course. And we estimate that that would translate to about, we think it's about one extra case of never smoking lung cancer per hundred thousand of the population per year per one microgram per meter cube rise in the pollution levels. So if you go to Beijing for example, on a bad day, the air pollution levels could be upwards of a hundred micrograms per meter cubed because there are so many coal fired power stations in China partly. And there I think the risk is considerably higher. And that's certainly what we've seen in the meta-analyses in our limited and relatively crude epidemiological analyses to be the case.(30:59):So I think the association was pretty certain, we were very confident from people's prior publications  this was important. But of course, association is not causation. So we took a number of animal models and showed that you could promote lung cancer formation in four different oncogene driven lung cancer models. And then the question is how, does air pollution stimulate mutations, which is what I initially thought it would do or something else. It turns out we don't see a significant increase in exogenous like C to A carcinogenic mutations. So that made us put our thinking caps on. And I said to you earlier, often all these discoveries have been made before. Well, Berenblum in 1947, first postulated that actually tumors are initiated through a two-step process, which we now know involves a sort of pre initiated cell with a mutation in that in itself is not sufficient to cause cancer.(31:58):But on top of that you need an inflammatory stimulus. So the question was then, well, okay, is inflammation working here? And we found that there was an interleukin-1 beta axis. And what happens is that the macrophages come into the lung on pollution exposure, engulf phagocytose the air pollutants, and we think what's happening is the air pollutants are puncturing membranes in the lung. That's what we think is happening. And interleukin-1 beta preformed IL-1 beta is being released into the extracellular matrix and then stimulating pre-initiated cells stem cells like the AT2 cells with an activating EGFR mutation to form a tumor. But the EGFR mutation alone is not sufficient to form tumors. It's only when you have the interleukin-1 beta and the activated mutation that a tumor can start.(32:49):And we found that if we sequence normal lung tissue in a healthy adult 60-year-old adult, we will find about half of biopsies will have an activating KRAS mutation in normal tissue, and about 15% will have an activating mutation in EGFR in histologically normal tissue with nerve and of cancer. In fact, my friend and colleague who's a co-author on the paper, James DeGregori, who you should speak to in Colorado, fascinating evolutionary cancer biologists estimates that in a healthy 60-year-old, there are a hundred billion cells in your body that harbor an oncogenic mutation. So that tells you that at the cellular level, cancer is an incredibly rare event and almost never happens. I mean, our lifetime risk of cancer is perhaps one in two. You covered that beautiful pancreas paper recently where they estimated that there may be 80 to 100 KRAS mutations in a normal adult pancreas, and yet our lifetime risk of pancreas cancer is one in 70. So this tells you that oncogenic mutations are rarely sufficient to drive cancer, so something else must be happening. And in the context of air pollution associated lung cancer, we think that's inflammation driven by these white cells, these myeloid cells, the macrophages.Cancer BiomarkersEric Topol (34:06):No, it makes a lot of sense. And this, you mentioned the pancreas paper and also what's going in the lung, and it seems like we have this burden of all you need is a tipping point and air pollution seems to qualify, and you seem to be really in the process of icing the mechanism. And like I would've thought it was just mutagenic and it's not so simple, right? But that gets me to this is such an important aspect of cancer, the fact that we harbor these kind of preconditions. And would you think that cancer takes decades to actually manifest most cancers, or do we really have an opportunity here to be able to track whether it's through blood or other biomarkers? Another area you've worked on a lot whereby let's say you could define people at risk for polygenic risk scores or various cancers or genome sequencing for predisposition genes, whatever, and you could monitor in the future over the course of those high-risk people, whether they were starting to manifest microscopic malignancy. Do you have any thoughts about how long it takes for the average person to actually manifest a typical cancer?Charles Swanton (35:28):That's a cracking question, and the answer is we've got some clues in various cancers. Peter Campbell would be a good person to speak to. He estimates that some of the earliest steps in renal cancer can occur in adolescence. We've had patients who gave up smoking 30 or so years ago where we can still see the clonal smoking mutations in the trunk of the tumor's evolutionary tree. So the initial footprints of the cancer are made 30 years before the cancer presents. That driver mutation itself may also be a KRAS mutation in a smoking cigarette context, G12C mutation. And those mutations can precede the diagnosis of the disease by decades. So the earliest steps in cancer evolution can occur, we think can precede diagnoses by a long time. So to your point, your question which is, is there an opportunity to intervene? I'm hugely optimistic about this actually, this idea of molecular cancer prevention.An Anti-Inflammatory Drug Reduces Fatal Cancer and Lung Cancer(36:41):How can we use data coming out of various studies in the pancreas, mesothelioma, lung, et cetera to understand the inflammatory responses? I don't think we can do very much about the mutations. The mutations unfortunately are a natural consequence of aging. You and I just sitting here talking for an hour will have accumulated multiple mutations in our bodies over that period, I'm afraid and there's no escaping it. And right now there's not much we can do to eradicate those mutant clones. So if we take that as almost an intractable problem, measuring them is hard enough, eradicating them is even harder. And then we go back to Berenblum in 1947 who said, you need an inflammatory stimulus. Well, could we do something about the inflammation and dampen down the inflammation? And of course, this is why we got so excited about IL-1 beta because of the CANTOS trial, which you may remember in 2017 from Ridker and colleagues showed that anti IL-1 beta used as a mechanism of preventing cardiovascular events was associated with a really impressive dose dependent reduction in new lung cancer primaries.(37:49):Really a beautiful example of cancer prevention in action. And that data weren't just a coincidence. The FDA mandated Novartis to collect the solid tumor data and the P-values are 0.001. I mean it's very highly significant dose dependent reduction in lung cancer incidents associated with anti IL-1 beta. So I think that's really the first clue in my mind that something can be done about this problem. And actually they had five years of follow-up, Eric. So that's something about that intervening period where you can treat and then over time see a reduction in new lung cancers forming. So I definitely think there's a window of opportunity here.Eric Topol (38:31):Well, what you're bringing up is fascinating here because this trial, which was a cardiology trial to try to reduce heart attacks, finds a reduction in cancer, and it's been lost. It's been buried. I mean, no one's using this therapy to prevent cancer between ratcheting up the immune system or decreasing inflammation. We have opportunities that we're not even attempting. Are there any trials that are trying to do this sort of thing?Charles Swanton (39:02):So this is the fundamental problem. Nobody wants to invest in prevention because essentially you are dealing with well individuals. It's like the vaccine challenge all over again. And the problem is you never know who you are benefiting. There's no economic model for it. So pharma just won't touch prevention with a barge pole right now. And that's the problem. There's no economic model for it. And yet the community, all my academic colleagues are crying out saying, this has got to be possible. This has got to be possible. So CRUK are putting together a group of like-minded individuals to see if we can do something here and we're gradually making progress, but it is tough.Eric Topol (39:43):And it's interesting that you bring that up because for GRAIL, one of the multicenter cancer early detection companies, they raised billions of dollars. And in fact, their largest trial is ongoing in the UK, but they haven't really focused on high-risk people. They just took anybody over age 50 or that sort of thing. But that's the only foray to try to reboot how we or make an early microscopic diagnosis of cancer and track people differently. And there's an opportunity there. You've written quite a bit on you and colleagues of the blood markers being able to find a cancer where well before, in fact, I was going to ask you about that is, do you think there's people that are not just having all these mutations every minute, every hour, but that are starting to have the early seeds of cancer, but because their immune system then subsequently kicks in that they basically kind of quash it for that period of time?Charles Swanton (40:47):Yeah, I do think that, I mean, the very fact that we see these sort of footprints in the tumor genome of immune evasion tells you that the immune system's having a very profound predatory effect on evolving tumors. So I do think it's very likely that there are tumors occurring that are suppressed by the immune system. There is a clear signature, a signal of negative selection in tumors where clones have been purified during their evolution by the immune system. So I think there's pretty strong evidence for that now. Obviously, it's very difficult to prove something existed when it doesn't now exist, but there absolutely is evidence for that. I think it raises the interesting question of immune system recognizes mutations and our bodies are replete with mutations as we were just discussing. Why is it that we're not just a sort of epithelial lining of autoimmunity with T-cells and immune cells everywhere? And I think what the clever thing about the immune system is it's evolved to target antigens only when they get above a certain burden. Otherwise, I think our epithelial lining, our skin, our guts, all of our tissues will be just full of T-cells eating away our normal clones.(42:09):These have to get to a certain size for antigen to be presented at a certain level for the immune system to recognize it. And it's only then that you get the immune predation occurring.Forever Chemicals and Microplastics Eric Topol (42:20):Yeah, well, I mean this is opportunities galore here. I also wanted to extend the air pollution story a bit. Obviously, we talked about particulate matter and there's ozone and nitric NO2, and there's all sorts of other air pollutants, but then there's also in the air and water these forever chemicals PFAS for abbreviation, and they seem to be incriminated like air pollution. Can you comment about that?Charles Swanton (42:55):Well, I can comment only insofar as to say I'm worried about the situation. Indeed, I'm worried about microplastics actually, and you actually cover that story as well in the New England Journal, the association of microplastics with plaque rupture and atheroma. And indeed, just as in parenthesis, I wanted to just quickly say we currently think the same mechanisms that are driving lung cancer are probably responsible for atheroma and possibly even neurodegenerative disease. And essentially it all comes down to the macrophages and the microglia becoming clogged up with these pollutants or environmental particulars and releasing chronic inflammatory mediators that ultimately lead to disease. And IL-1 beta being one of those in atheroma and probably IL-6 and TNF in neurodegenerative disease and what have you. But I think this issue that you rightly bring up of what is in our environment and how does it cause pathology is really something that epidemiologists have spent a lot of time focusing on.(43:56):But actually in terms of trying to move from association to causation, we've been, I would argue a little bit slow biologically in trying to understand these issues. And I think that is a concern. I mean, to give you an example, Allan Balmain, who works at UCSF quite close to you, published a paper in 2020 showing that 17 out of 20 environmental carcinogens IARC carcinogens class one carcinogens cause tumors in rodent models without driving mutations. So if you take that to a logical conclusion, in my mind, what worries me is that many of the sort of carcinogen assays are based on driving mutagenesis genome instability. But if many carcinogen aren't driving DNA mutagenesis but are still driving cancer, how are they doing it? And do we actually have the right assays to interpret safety of new chemical matter that's being introduced into our environment, these long-lived particles that we're breathing in plastics, pollutants, you name it, until we have the right biological assays, deeming something to be safe I think is tricky.Eric Topol (45:11):Absolutely. And I share your concerns on the nanoplastic microplastic story, as you well know, not only have they been seen in arteries that are inflamed and in blood clots and in various tissues, have they been seen so far or even looked for within tumor tissue?Charles Swanton (45:33):Good question. I'm not sure they have. I need to check. What I can tell you is we've been doing some experiments in the lab with fluorescent microplastics, 2.5 micron microplastics given inhaled microplastics. We find them in every mouse organ a week after. And these pollutants even get through into the brain through the olfactory bulb we think.Charles Swanton (45:57):Permeate every tissue, Eric.Eric Topol (45:59):Yeah, no, this is scary because here we are, we have these potentially ingenious ways to prevent cancer in the future, but we're chasing our tails by not doing anything to deal with our environment.Charles Swanton (46:11):I think that's right. I totally agree. Yeah.Eric Topol (46:15):So I mean, I can talk to you for the rest of the day, but I do want to end up with a topic that we have mutual interest in, which is AI. And also along with that, when you mentioned about aging, I'd like to get your views on these two, how do you see AI fitting into the future of cancer? And then the more general topic is, can we actually at some point modulate the biologic aging process with or without help with from AI? So those are two very dense questions, but maybe you can take us through them.Charles Swanton (46:57):How long have we got?Eric Topol (46:59):Just however long you have.A.I. and CancerCharles Swanton (47:02):AI and cancer. Well, AI and medicine actually in general, whether it's biomedical research or medical care, has just infinite potential. And I'm very, very excited about it. I think what excites me about AI is it's almost the infinite possibilities to work across scale. Some of the challenges we raised in the Cell review that you mentioned, tackling, embracing complexity are perfectly suited for an AI problem. Nonlinear data working, for instance in our fields with CT imaging, MRI imaging, clinical outcome data, blood parameters, genomics, transcriptomes and proteomes and trying to relate this all into something that's understandable that relates to risk of disease or potential identification of a new drug target, for example. There are numerous publications that you and others have covered that allude to the incredible possibilities there that are leading to, for instance, the new identification of drug targets. I mean, Eli Van Allen's published some beautiful work here and in the context of prostate cancer with MDM4 and FGF receptor molecules being intimately related to disease biology.(48:18):But then it's not just that, not just drug target identification, it's also going all the way through to the clinic through drug discovery. It's how you get these small molecules to interact with oncogenic proteins and to inhibit them. And there are some really spectacular developments going on in, for instance, time resolved cryo-electron microscopy, where in combination with modeling and quantum computing and what have you, you can start to find pockets emerging in mutant proteins, but not the wild type ones that are druggable. And then you can use sort of synthetic AI driven libraries to find small molecules that will be predicted to bind these transiently emerging pockets. So it's almost like AI is primed to help at every stage in scientific investigation from the bench all the way through to the bedside. And there are examples all the way through there in the literature that you and others have covered in the last few years. So I could not be more excited about that.Eric Topol (49:29):I couldn't agree with you more. And I think when we get to multimodal AI at the individual level across all their risks for conditions in their future, I hope someday will fulfill that fantasy of primary prevention. And that is getting me to this point that I touched on because I do think they interact to some degree AI and then will we ever be able to have an impact on aging? Most people conflate this because what we've been talking about throughout the hour has been age-related diseases, that is cancer, for example, and cardiovascular and neurodegenerative, which is different than changing aging per se, body wide aging. Do you think we'll ever changed body wide aging?Charles Swanton (50:18):Wow, what a question. Well, if you'd asked me 10 years ago, 15 years ago, do you think we'll ever cure melanoma in my lifetime, I'd have said definitely not. And now look where we are. Half of patients with melanoma, advanced melanoma, even with brain metastasis curd with combination checkpoint therapy. So I never say never in biology anymore. It always comes back to bite you and prove you wrong. So I think it's perfectly possible.Charles Swanton (50:49):We have ways to slow down the aging process. I guess the question is what will be the consequences of that?Eric Topol (50:55):That's what I was going to ask you, because all these things like epigenetic reprogramming and senolytic drugs, and they seem to at least pose some risk for cancer.Charles Swanton (51:09):That's the problem. This is an evolutionary phenomenon. It's a sort of biological response to the onslaught of these malignant cells that are potentially occurring every day in our normal tissue. And so, by tackling one problem, do we create another? And I think that's going to be the big challenge over the next 50 years.Eric Topol (51:31):Yeah, and I think your point about the multi-decade challenge, because if you can promote healthy aging without any risk of cancer, that would be great. But if the tradeoff is close, it's not going to be very favorable. That seems to be the main liability of modulation aging through many of the, there's many shots on goal here, of course, as you well know. But they do seem to pose that risk in general.Charles Swanton (51:58):I think that's right. I think the other thing is, I still find, I don't know if you agree with me, but it is an immense conundrum. What is the underlying molecular basis for somatic aging, for aging of normal tissues? And it may be multifactorial, it may not be just one answer to that question. And different tissues may age in different ways. I don't know. It's a fascinating area of biology, but I think it really needs to be studied more because as you say, it underpins all of these diseases we've been talking about today, cardiovascular, neurodegeneration, cancer, you name it. We absolutely have to understand this. And actually, the more I work in cancer, the more I feel like actually what I'm working on is aging.(52:48):And this is something that James DeGregori and I have discussed a lot. There's an observation that in medicine around patients with alpha-1 antitrypsin deficiency who are at higher risk of lung cancer, but they're also at high risk of COPD, and we know the associations of chronic obstructive pulmonary disease with lung cancer risk. And one of the theories that James had, and I think this is a beautiful idea, actually, is as our tissues age, and COPD is a reflection of aging, to some extent gone wrong. And as our tissues age, they become less good at controlling the expansion of these premalignant clones, harboring, harboring oncogenic mutations in normal tissue. And as those premalignant clones expand, the substrate for evolution also expands. So there's more likely to be a second and third hit genetically. So it may be by disrupting the extracellular matrices through inflammation that triggers COPD through alpha-1 antitrypsin deficiency or smoking, et cetera, you are less effectively controlling these emergent clones that just expand with age, which I think is a fascinating idea actually.Eric Topol (54:01):It really is. Well, I want to tell you, Charlie, this has been the most fascinating, exhilarating discussion I've ever had on cancer. I mean, really, I am indebted to you because not just all the work you've done, but your ability to really express it, articulate it in a way that hopefully everyone can understand who's listening or reading the transcript. So we'll keep following what you're doing because you're doing a lot of stuff. I can't thank you enough for joining me today, and you've given me lots of things to think about. I hope the people that are listening or reading feel the same way. I mean, this has been so mind bending in many respects. We're indebted to you.Charles Swanton (54:49):Well, we all love reading your Twitter feeds. Keep them coming. It helps us keep a broader view of medicine and biological research, not just cancer, which is why I love it so much.******************************************The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

What are the prospects for any progress at next week's peace summit in Switzerland, especially if Russia is not there? Our Russia editor, Steve Rosenberg and international editor, Jeremy Bowen give us their thoughts and also answer questions on Russia's economy, whether Russians are worried about Western missiles and how Ukrainian journalists are covering the war.Today's episode is presented by Victoria Derbyshire. Today's episode was produced by Clare Williamson with Paige Neal-Holder and Bella Saltiel . The technical producer was Gabriel O Regan. The series producer is Tim Walklate and the senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Dr. Diwakar Davar and Dr. Jason Luke discuss key abstracts from the 2024 ASCO Annual Meeting that explore triplet therapy in advanced melanoma, TIL cell therapy in immune checkpoint inhibitor–naive patients, and other novel approaches that could shape the future of immunotherapy in melanoma and beyond.  TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to have my friend and colleague, Dr. Jason Luke, on the podcast today to discuss key abstracts in melanoma and immunotherapy that will be featured and highlighted at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapeutic Center, as well as the associate director for clinical research at the University of Pittsburgh's Hillman Cancer Center.  You will find our full disclosures in the transcript of this episode.  Jason, as always, it's a pleasure to have you on this podcast to hear your key insights on trials in the immunotherapy space and melanoma development paradigm, and to have you back on this podcast to highlight some of this work.  Dr. Jason Luke: Thanks so much for the opportunity to participate. I always enjoy this heading into ASCO.  Dr. Diwakar Davar: We're going to go ahead and talk about three abstracts in the melanoma space, and we will be starting with Abstract 9504. Abstract 9504 essentially is the RELATIVITY-048 study. It describes the efficacy and safety of the triplet nivolumab, relatlimab, and ipilimumab regimen in advanced PD-1 naive melanoma. So in this abstract highlighted by Dr. Ascierto and colleagues, they report on the results of this phase 2 trial in this setting. By way of background, PD-1 inhibitors and immune checkpoint inhibitors starting in PD-1 and CTLA-4, as well as PD-1 and LAG-3, are all FDA-approved on the basis of several pivotal phase 3 trials, including KEYNOTE-006, CheckMate-066, CheckMate-067, and most recently, RELATIVITY-047. Jason, can you briefly summarize for this audience what we know about each of these drugs, at least the two combinations that we have at this time?  Dr. Jason Luke: For sure. And of course, these anti PD-1 agents, became a backbone in oncology and in melanoma dating back to more than 10 years ago now, that response rates in the treatment-naive setting to anti PD-1 with either pembrolizumab or nivolumab are roughly in the range of mid-30s to high-40s. And we've seen clinical trials adding on second agents. You alluded to them with the seminal study being CheckMate-067, where we combined a PD-1 antibody and CTLA-4 antibody or nivo + ipi. And there the response rate was increased to approximately 56%. And more recently, we have data combining PD-1 inhibitors with anti-LAG-3. So that's nivolumab and relatlimab. Now, in that trial, RELATIVITY-047, the overall response rate was described as 43%. And so that sounds, on a first pass, like a lower number, of course, than what we heard for nivolumab and ipilimumab. We have to be cautious, however, that the cross-trial comparison between those studies is somewhat fraught due to different patient populations and different study design. So I think most of us think that the response rate or the long-term outcomes between PD-1, CTLA-4, and PD-1 LAG-3 are probably roughly similar, albeit that, of course, we have much better or much longer follow up for the nivo + ipi combo.  The one other caveat to this, of course then, is that the side effect profile of these two combinations is distinct, where the incidence of high-grade immune-related adverse events is going to be roughly half with nivolumab and relatlimab, a combination of what you would see with the nivolumab and ipilimumab. So that has caused a lot of us to try to think about where we would use these different combinations. But we do see that all of these treatments can land a durable long-term response in the subset of patients that do have an initial treatment benefit. The landmark, I think, for the field has been the 7-and-a-half-year median overall survival that we've seen with PD-1 plus CTLA-4, nivo + ipi; of course, we don't have such long-term follow up for PD-1 and LAG-3. But I think that's the setting for thinking about the rationale for combining a triplet regimen of PD-1, CTLA-4, and LAG-3. Dr. Diwakar Davar: So, Jason, in your mind, given the difference in the disparity and durability of the responses for the 067 regimen of nivo-ipi, and the RELATIVITY-047 regiment of nivo-rela, what is the standard of care in the U.S., and how does it change in the rest of the world, knowing that nivo-rela is not necessarily approved in all jurisdictions? Dr. Jason Luke: So this is a major complication in our field, is that there is perhaps not complete agreement across the world in terms of what the frontline standard of care should be. I think most United States investigators, or those of us that really treat melanoma most of the time, would suggest that a combination regimen, given the enhanced response rate and longer-term outcomes, should be the consideration for the majority of patients. In fact, in my practice, it's hard to think of who I would treat with a monotherapy PD-1 approach in the PD-1 naive setting. So either nivo + ipi or nivo + rela. As you alluded to however, in other regulatory settings throughout the world, combinations might not actually even be approved at this point. So PD-1 monotherapy would be the backbone of that setting. It does set up some complications when you think about a comparator arm; say you were going to look at various combinations, probably PD-1 monotherapy would be the worldwide comparator. You have to understand though, in the United States, I think that that's a less attractive option. Dr. Diwakar Davar: So in RELATIVITY-047, Dr. Ascierto and his colleagues are looking at generating a triplet. And in this case, they looked at this in the context of frontline metastatic melanoma, 46 patients. Very interestingly, the dose of ipilimumab studied here was 1 mg/kg through 8 weeks, not the 3 mg/kg every three weeks times four doses using 067, or even the low dose ipilimumab regimen that you studied in the second line setting, which was 1 mg/kg every 3 weeks for 4 doses. So let's talk about the results and specifically the implications of potentially studying lower doses of ipi. Dr. Jason Luke: I appreciate you raising that point. I think it's really important as we think about this dataset because this triplet regimen is not by any means the only version of a triplet that could be developed using these agents. So just to give the high-level numbers from the abstract, we see from these data that the overall response rate is described as 59% and 78%, a disease control rate with patients having an unreached link. So duration of response of unreached, and then the progression-free survival at about 5 months. So those are really interesting data. But as was alluded to, it's not totally clear to me that that's the best that we could do with this regimen.   Now, you alluded to this low-dose ipilimumab schedule at 1 mg/kg every 8 weeks, and it's really important to note that we have no benchmark for that regimen in melanoma oncology. And in fact, the one study that used that regimen, which was the adjuvant study of nivolumab and ipilimumab, known as CheckMate915, is in fact the only immune checkpoint inhibitor study in melanoma oncology that was actually negative. That study noted no benefit to adding ipilimumab at 1 mg/kg every 8 weeks on top of nivolumab, again, the adjuvant setting. So it's a little bit curious to then understand what it means in this study to have that amount of ipilimumab added to the rela-nivo backbone. And that manifests in a few different ways. We see the response rate here at 59%. Again, if you compare that just against the standard nivo + ipi dosing schedule, it's about the same. So is that really an advantage to having the triplet as compared to just doing standard nivo + ipi?   We do see that it manifests in a slightly lower rate of grade 3/4 immune-related adverse events, at 39%. That's a little bit lower than what we'd expect for standard nivo + ipi. But again, I think that that emphasizes to me the possibility that some efficacy was left on the table by using this very low dose ipilimumab regimen. I think that's really a concern. It's not clear to me that these triplet data really differentiate from what we'd expect with the already approved regimen of nivo + ipi. Therefore, it makes it difficult to think about how would we really want to move this regimen forward, or should there be more work done about dose and schedule to optimize how we might want to do this?  Dr. Diwakar Davar: As far as triplet therapy in the context of frontline metastatic melanoma, meaning triplet immune therapy, because there are at least several targeted therapy triplets that are FDA-approved, [but] not necessarily widely utilized. How would you summarize the future for triplet therapy? Do you think it's potentially attractive? Do you think it's very attractive with some caveats? Dr. Jason Luke: Well, I think it's attractive, and we have 3 independently active agents. And so I do think it's a priority for the field to try to figure out how we could optimize the therapy. We've had such a revolution in melanoma oncology, talking about 7.5-year median survival from CheckMate-067, but that still implies that 7.5 years, half the patients have passed away. There's more to do here. And so I do think it should be a priority to sort this out. I guess I would be cautious, though, about advancing this regimen directly to a phase 3 trial because it doesn't seem clear to me that this is optimized in terms of what the outcome could be. If we're willing to tolerate higher rates of toxicity from other dose schedules of nivo-ipi alone, then I think we should do a little bit more here to potentially explore the space that might be possible to increase that overall response rate a little more without getting into a completely exaggerated toxicity profile that would be unacceptable. So, I do think it's exciting, but there's possibly more to do before really think about going big time with this. Dr. Diwakar Davar: Great. So now we'll switch gears and move from frontline metastatic melanoma to the second line and beyond looking at a new agent and contextualizing the effects of that actually in the frontline settings. So Abstract 9505 describes the efficacy and safety of lifileucel, which is essentially autologous tumor-infiltrating lymphocyte cell therapies, also known as TIL, in combination with pembrolizumab in patients with ICI naive, so not necessarily pretreated, but ICI naive metastatic or unresectable melanoma. This is data from the IOV-COM-202 Cohort 1A oral abstract presented by Dr. Thomas and colleagues. In this abstract, Dr. Thomas and colleagues are presenting data from the 1A cohort, which is the phase 2 portion of the frontline trial that is evaluating autologous TIL with pembro in checkpoint inhibited naive metastatic melanoma.  By way of background, TIL is FDA approved on the basis of several cohorts from a phase 2 trial. The data has been presented multiple times now by Drs. Sarli, Chesney, and multiple colleagues of ours. And essentially autologous TIL, which is generated from a surgical procedure in which a patient undergoes a surgery to extract a tumor from which T cells are then grown after ex vivo expansion and rapid expansion protocol. The entire procedure was essentially pioneered by several colleagues at the NCI, primarily Dr. Steve Rosenberg, and this approach produces objective response rates of approximately 31% to 36%. And the most recent publication demonstrated that at median follow up of approximately 2 years, the median duration of response was not reached. The median OS was about 14 months and PFS was about 4 months or so. So, can you contextualize the results of the abstract in the frontline setting? And then we'll talk a little bit about where we think this is going to go. Dr. Jason Luke: So I think this is a timely study given the recent approval. And in the abstract presented here, we see an early data cut from the PD-1 naive study, as you alluded to. So here we had 22 patients and distributed across various states of advanced melanoma. Ten out of the 22 had M1C, but there also were smatterings of earlier M1A and M1B at 18.2% and 9.1%. So this is important, as we think who the treatment population is that's going to be optimized with a TIL procedure. The median sum of diameters, meaning how much tumor burden the patients have, was about 5.5cm, and I'll note that that's a relatively modest amount of tumor burden, albeit not that unusual for an early-stage trial. So of the patients that participated, 8 had BRAF mutations so that's 36%. That's not that high, but it's reasonable. And I think the important overlying number, the response rate so far in the study, with about 17 months of follow up, was 63.6%, and that includes 22% or 23% having complete response. So those are interesting data.  And another point that was made in the abstract, which we've all seen, is that responses to TIL, all of immunotherapy but especially TIL, do seem to mature over time, meaning they deepen over time. So it's possible the response rate could go up some extent as we watch this study advance. So I think these are exciting data on some level. Also, a 63.6% response rate sounds pretty impressive, but we do have to put that in the context of a double checkpoint blockade, which we just got done discussing, gives you almost a 60% response rate, 59% response rate. So then the question really is: Is it worth the amount of effort that we could go into generating a TIL product in a treatment naive patient, and put them through the lymphodepletion that is associated with TIL and the high dose interleukin 2 treatment that accompanies the reinfusion of the TIL, if you're going to get a response rate that's roughly the same as what you would get if you gave them off the shelf nivo plus ipilimumab?  At this point it's a little bit hard to know the answer to that question. I think it could be possible that the answer is yes, because we don't know exactly which populations or patients are most likely to benefit from each of these therapies. And if it could be teased out who's not going to benefit to nivo + ipi from the get-go, then of course, we would want to offer them a therapy that has that frontline potential, durable, long-term response. But I have to say, on a one-to-one with TIL therapy, you get a lot of toxicity initially with the treatment; with nivo + ipi on the back end, you get a fair amount of toxicity with the treatment. How are we going to judge those two things? And I think we probably need a larger dataset to really have a good handle on that.  So these are interesting early data, but it's not totally clear to me that even if this holds up all the way through the trial, and we're going to talk about the design of the registration trial here in a second, a 60% response rate on its own without further biomarker stratification is a little bit hard for me to see in clinical practice why we would want to do that, given we can already just go off the shelf and give checkpoint inhibitors. Dr. Diwakar Davar: So that brings us to TILVANCE-301. So TILVANCE is a phase 3 trial. It's a registration intent trial by our Iovance colleagues evaluating the pembro-TIL regimen versus pembrolizumab alone. So in this phase 3 trial, approximately 670 patients will be randomized to either arm A, which is lifileucel + pembro. And in this arm A, patients are going to be getting lifileucel with the tumor resection, non-myeloablative lymphoid depletion, the lifileucel and abbreviated course of high-dose IL-2, and thereafter, continued pembro for the study mandated duration versus arm B, where patients will be getting just pembrolizumab monotherapy per label. Arm B patients, per the design, may cross over to receive TIL monotherapy at the time of central-blinded, radiology-confirmed disease progression.   The study design otherwise is fairly routine and, per most of our registration trials these days, patients have actually been permitted to receive neoadjuvant and adjuvant therapy, including checkpoint inhibitors, as long as the receipt of the therapy was more than 6 months prior to the inclusion of the patient in that registration trial. The dual primary efficacy endpoints as stated are BICR-assessed objective response rate as well as PFS, and the key secondary endpoint is overall survival.   So Jason, what are your thoughts on the study design and potentially the regulatory implications, particularly given, one, the control arm of pembro monotherapy, and two, the role of TIL crossover to receive TIL monotherapy at the time of BICR mandated progression for arm B? Dr. Jason Luke: So this goes to a few points that we've touched on already in the discussion here. When we think about the primary endpoints for this study, with one of them being overall response rate, one has to assume that that's a given that they would get that. I feel like that's a low bar. And we go back to that cross-trial comparison. If their results end up being that the response rates are about 60%, I don't know that that differentiates necessarily from what's already available in the field with combination immune checkpoint blockade. For the purposes of the study that would mean it's a positive study, so I think that would probably be good. But again, the comparator to pembrolizumab monotherapy, I think some of us would argue, isn't really consistent with what we would do with a patient in our clinic. So it's not that it's bad per se, but I think there's going to be a whole lot of cross-trial comparison. So if the study is positive, that would be good for getting the drug available. It's still a bit hard though, based on the preliminary data that I've seen, to imagine how this would have uptake in terms of utilization as a frontline therapy.  You alluded to the crossover, and I think there, the assumption is that patients who get TIL therapy as a second line perhaps would have an attenuated benefit. But I'm not sure that's really true. It certainly looks from the data that we have, like the patients who benefit most from TIL are going to be those who didn't respond to anti PD-1 in the front line. So I'm not sure how much difference there's going to be between first- and second-line TIL therapy, but those data will kind of wait to be seen. So I think it's an important study. Of course, the accelerated approval of TIL as a later line therapy is dependent on this trial being positive. So there is some risk that if this trial ended up not being positive, that that could have regulatory implications on the utility or availability of TILs, a subsequent line therapy. But all of these, I guess we'll have to wait to see the results. We do hope for a positive trial here, although I think it'll be nuanced to sort of interpret those data given that pembrolizumab monotherapy control arm.  Dr. Diwakar Davar: Fantastic. So we've learned a lot about TIL, both its use in the second-line setting and this very exciting but potentially risky frontline trial that is ongoing at some centers in the United States and certainly a lot of ex-U.S. enrollment.   So we'll now pivot to a related product which actually belongs to a much larger class of agents that are antigen specific T-cell therapies in a variety of different formats. And that is Abstract 9507, which is the “Phase 1 safety and efficacy of IMC-F106C, a PRAME × CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM).” Now, in this abstract, Dr. Omid Hamid and colleagues reported the results of this phase 1 trial. As a disclosure, I'm an investigator and the last author on this manuscript. Jason, it would be important for our audience, for us to maybe firstly, outline the PRAME as a target, and then the ImmTAC as a platform prior to discussing these results. So let's start with the target PRAME, which I think is a target that you know well. So why don't you start with the target and we'll talk a little bit about that and then the platform? Dr. Jason Luke: Yeah, so I think for the audience, being aware of PRAME, or the Preferentially Expressed Antigen in Melanoma, is going to be quite important moving into the future. So PRAME as a therapeutic target is a cancer testis antigen that's overexpressed in tumor tissues. And of course the name has melanoma in it, but it's not uniquely present in melanoma. So the expression patterns of PRAME as a target are very high in melanoma. So in cutaneous disease, this is upwards of almost 100%, somewhere between 95% and 100%, in metastatic melanoma tissues. And PRAME has several different roles on a molecular level, although I don't think for our purposes here, it's so much important to be aware of them, but rather that this is a very highly expressed target, which then can make it attractive for using T cell receptor-based therapies. And so in the case we're talking about here on the ImmTAC platform, that's a CD3 PRAME×CD3 bispecific approach. But of course there are other approaches that can also be taken, such as TCR T cells that directly go after PRAME itself. Dr. Diwakar Davar: Let's now talk about the platform and how it differs from some of the other antigen targeting platforms that you have just alluded to. I think the Immtac platform is basically a fusion protein comprising engineered TCRs with a CD3 specific short chain variable fragment. And then the engineered TCR therefore binds antigens in an HLA dependent fashion. But you know quite a lot about some of these alternative platforms, and I think it'll be important to contextualize for the audience the difference between ImmTAC, which is a prototype drug that is already approved in the context of tebentafusp. But how does this differ from some of the other more nuanced platforms, such as the Immatics TCR or TCR platform and TScan TCRT nanoplasmonic platform.  Dr. Jason Luke: Right. So the ImmTAC platform as alluded to is already approved on the market with tebentafusp, which is the gp100-CD3 bispecific molecule. And the advantage of that approach is infusion off the shelf of a drug. The downside of it is that it is a weekly dosing strategy as it stands now. And there are some complicated disease kinetics associated with treatment response, which we'll come back to in the context of the PRAME bispecific. Those are, in contrast with T-cell receptor-transduced T cells, as an alternative strategy, which is a form of adopted cell transfer. So we just got done talking about TIL therapy, which of course, is trying to take lymphocytes out of the tumor and grow them up and then give them back. Here with TCR-transduced T cells, we're talking about taking leukopak from the blood and then using different transfection approaches to try to insert into the lymphocytes of the patient a T cell receptor that recognizes to a certain cancer antigen, in this case, PRAME.  So you alluded to a couple of different companies that have different platforms to do this. Immatics has a molecule called IMA 203, for which there have been data disclosed in the past year, again showing some very interesting responses in patients who have highly refractory melanoma. That process, though, again, does require lymphodepletion before you reinfuse the cells. Again, in contrast, the ImmTAC, which is an off the shelf revenue administer, there you have to make the product and then bring the patient back, lymphodeplete, and give the cells back. Immatics platform uses a viral transfection vector. The T scan approach that you alluded to before uses an approach of a mixed system on multiple HLA backgrounds to try to get past HLA-A*02:01 only, and in this case, uses a plasmid-based transfection syndrome that perhaps can be more broadly utilized given the lack of a lentiviral vector.   So this is a complicated area of technology that starts to get into immune engineering, and I think for the purposes of this discussion, we don't want to belabor it. But both of these technologies, talking about the CD3 bispecific with the off the shelf aspect of it and the adoptive cell transfer, each of these using a T cell receptor-based therapy to try to go after PRAME, I think have very high upsides, and I think we'll initially see it in melanoma over the next year or so. But this is likely to be relevant to multiple tumor types beyond melanoma.  Dr. Diwakar Davar: So let's discuss the results of this phase 1 trial. IMC-F106C, like all other ImmTAC, is administered intravenously and does require step-up dosing. You alluded to the fact that the tebentafusp was approved, and it's one of those drugs that is fortunately otherwise administered weekly, which can be difficult for the patient and requires at least the patient spend the first 3 doses overnight under some kind of monitoring, whether it's in the hospital or extended outpatient monitoring, for at least 23 hours. The efficacy of this agent and this platform appears to be surprising in that you tend to see a relatively low RECIST response rate. We'll have you comment a little bit on why that is the case and what may be the role of ctDNA, as opposed to conventional RECIST in assessing response.   At least in this trial, they mandated pre-testing, but did not require it for study enrollment. And pre-positivity was defined using immunohistochemistry with a relatively low H-score of 1%. And the molecular response definition was a 0.5 log or a 68% ctDNA reduction just prior to the first imaging assessment. So how do you contextualize the results? But maybe before you talk a little bit about the results, the ctDNA aspect, that was a recent publication by Drs. Rich Carvajal, Alex Shoushtari, and I think you are also involved in that.  Dr. Jason Luke: So, I think an interesting observation around tebentafusp has been that ctDNA may be a better predictor of long-term outcomes. And how you define ctDNA response is still something that the field is grappling with, albeit that I think is going to be an important consideration as we think about these novel therapies, these ImmTACs and other CD3 engagers moving into the future. But for the purposes of the abstract here, we see that in the population of patients treated, there were 46 patients with cutaneous melanoma. The majority got monotherapy with IMC-F106C, and that's the PRAME bispecific. So 40 patients that got monotherapy and six who got a combination with checkpoint inhibitor. All these patients had prior treatment with immunotherapy, and most of them had PD-1 and CTLA-4 antibody with a small spanner that also had BRAF inhibitors.  In terms of that PRAME testing that you alluded to, based on the immunohistochemistry H-score greater than 1%, 35 out of 40 patients were positive, so they defined 5 as negative. And we could come back if we have time, but there are other ways to do PRAME testing as well that I think may become unique for different agents, maybe an important biomarker. In the data, 31 out of the 46 patients were RECIST evaluable. The outcomes of those patients were to note that the response rate was 13%, which was four partial responses. But 35% of patients had tumor regression with a disease control rate at 65%. It was clear that there was an enrichment by PRAME positivity for both progression free and overall survival. So those patients who had obvious positivity essentially had a doubling of the PFS and more than the doubling of the OS, 2.1 to 4.1 months for TFS and landmark OS, 40% to 94%. So I think these are quite intriguing data.  It does suggest that for the vast majority of patients, we do see some induction of the antitumor effect, albeit that RECIST might undercall the effect. And so this may become another area where the ctDNA monitoring might be able to help us to understand who is likely to have really long-term benefit from this therapy. And given the number of emerging treatments that we have for melanoma, we might be able to really focus in on that group of patients in terms of optimizing how we would use this drug moving into the future. Dr. Diwakar Davar: So you talked about a response rate, and at first glance, this response rate is a little underwhelming. We're talking about 4 out of 31 RECIST evaluable patients, 13%. So it's in the double digits, but barely. So how enthusiastic are you about the results? How does it contrast with at least the publicly known data from other brain targeting approaches, such as the IMA203 agent, understanding that while they may be all targeting somewhat the same target, they are actually extraordinarily different platforms. One's off the shelf, one's highly customized. How do you contextualize the results? How would it contrast with other cellular approaches?  Dr. Jason Luke: I think it's important, again, to emphasize the point you made, which is that they're very different kinds of treatments. So even though they both target PRAME, they're going to be differently useful, and they could be quite useful for different groups of patients. And so here we see that there is a subfraction of patients who are deriving long-term benefit. And we commonly have an argument in our field about, is overall response rate really a useful monitor that describes a patient-centric outcome? While, of course, patients like to know their tumors are shrinking, what they want the most is for the tumors not to get worse and for them not to pass away from cancer. So I think I'm enthusiastic about these results, but emphasizing the point that we need to better understand who is going to benefit the most from this CD3 bispecific PRAME approach and how we're going to be able to harness that into long term benefit for patients because there's no doubt that an off the shelf therapy has a high degree of value relative to adoptive cell transfer, which sort of requires a big wind up.   So when you say, what does it contrast with? Well, the data for IMA203 has shown more than a 50% response rate in patients with more than 5 lines of therapy for metastatic disease. That really looks quite exciting. And several of those patients are now out for quite an extended period, meaning 2 years or more given only a single dose of IMA203. But again, the caveat being, you have to make the cell product for the patient, and that takes time. You lymphodeplete the patient, not all patients can tolerate that in the refractory disease setting, and then they have to be able to tolerate the reinfusion of the cells. And so this drug, IMC-F106C, looks very promising. Moving into the earlier phase trial that we'll talk about, I think the TCR T cell program has a lot of upsides for patients, especially with refractory disease. And so I think these two different approaches are really on parallel tracks. They both target PRAME, but I don't think they necessarily need to be compared one to one, as if they're going to go head-to-head with each other. Dr. Diwakar Davar: So now we'll talk a little bit about the frontline setting, because on the basis of some of these results, Immunocore is now exploring IMC-F106C frontline melanoma. This trial is actually being presented as a trial in progress at this meeting by Georgina Long and colleagues. Some of us are co-authors in that abstract. And in this study, HLA-A*02:01 positive patients with advanced unresectable melanoma will be randomized one to one to the combination of IMC-F106C, which actually, I think after this meeting will be known as bre-ni in combination with nivolumab versus nivolumab regimens, which will either be nivo or nivo-rela, investigators choice and likely dependent on region. So what do you think of the challenge of this trial? We talked about some of the challenges of the TILVANCE trial earlier. But what is going to be the challenge of this trial and in this setting, particularly given the response rates that we've seen so far? Dr. Jason Luke: Yeah, so, similar to comments we had before, thinking about what the optimal control arm is for a study like this is difficult, and so that'll be important as we think about interpreting the results. One has to assume for the purpose of this conversation that it is a positive trial, and that adding the PRAME bispecific theory does lead to an improvement in progression free survival relative to those in checkpoint alone approaches. And I think the magnitude of that difference is going to be of some relevance. And then I think importantly, also figure out who needs this treatment and who's going to benefit long term are going to be really important considerations.  We alluded to how this drug requires an intensive dosing period at the get go, and so telling patients that they need to come in weekly or bi-weekly initially for some number of weeks before they switch to a longer-term intermittent regimen, that comes with real world considerations for patients, their families, their finances, etc. So the benefit has to be clearly obvious that makes it worthwhile doing that, again, because a default could be giving drugs that we've had for 10 years with the nivolumab and ipilimumab. So there's going to be a lot of cross-trial comparison that is going to necessarily have to take place here to think about what these results really mean in the context of other available therapies.  I think the study is reasonable to do. I think this is a very active agent. There's no doubt there's a subset of patients who seem to benefit a lot from it. And I would just emphasize the point that that's probably going to be the most important thing to really drill down on is under the assumption there's a positive trial, we need to know who those people are so we could optimize giving this kind of a treatment to them. Dr. Diwakar Davar: I guess one important point to underscore what Jason said about potential predictive biomarkers, I think as part of the presentation, Dr. Hamid and colleagues will be talking about a candidate predictive biomarker of this agent, which is potentially class specific and not necessarily agent specific of a T cell signature that potentially could define patients who are more likely to benefit from this agent.  So, Jason, as always, thank you for sharing your expertise and insights with the team today. We certainly look forward to catching up again for our wrap up episode after the annual meeting where we'll talk about some of the data that we could not talk about, particularly the late breaking abstracts and other key advances that will shape the future of, certainly the field of immunotherapy and melanoma, potentially the field of cancer immunotherapy at large. Dr. Jason Luke: Oh, thanks very much for the opportunity. Dr. Diwakar Davar: And thank you to our listeners today. You'll find the links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. So thank you, and we'll see you soon.   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. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio      

Vladimir Putin has been sworn in as Russia's president for a new six-year term, just days before Russia's annual Victory Day military parade on 9 May.But why does this annual event, marking victory over Nazi Germany in 1945, matter so much to Russia now?We speak to Alexander Goncharov a former Russian military officer, who's now head of the World War Two veterans organisation in Moscow.And we discuss Victory Day's symbolism with Russia editor Steve Rosenberg and Patricia Lewis from Chatham House.Today's episode is presented by Jamie Coomarasamy and Vitaly Shevchenko. The producers were Charlie Henry and Arsenii Sokolov. The technical producer was Mike Regaard. The series producer is Tim Walklate. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

We answer your questions on the US aid package for Ukraine: when will it be felt on the frontline and will it have an impact on the war?To help do this Victoria and Vitaly are joined by the former head of the US Army in Europe, General Ben Hodges, who also gives his assessment on whether Ukraine can win.And, we hear from Steve Rosenberg in Moscow who shares some news about his friend Valentina, who used to work in a newspaper kiosk.Today's episode is presented by Victoria Derbyshire and Vitaly Shevchenko. The producers were Arsenii Sokolov, Cordelia Hemming, Elliot Ryder and Miriam Quayyum. The technical producer was Mike Regaard. The series producer is Tim Walklate. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

In this episode, Ann Carden is joined by Steve Rosenberg, who shares his unique networking approach and career transition. They delve into key lessons from Steve's book "Make Bold Things Happen" and discuss strategies for overcoming fear. They also touch on the pandemic's impact on businesses, redefine personal success, and explore the concept of quitting. Towards the end, Steve shares how to live your best life and the power of recognition.

Steve Rosenberg, Russia Editor for BBC News, on the Moscow concert hall attack on Friday night, and what Vladimir Putin is likely to do next.

Kate Adie introduces stories from Russia, Germany, Timor Leste and OmanAt a recent gathering in a gilded hall in the Kremlin, Vladimir Putin thanked VIP supporters for his re-election. As he commenced his fifth term in office, he has reminded his voters that the annexation of Crimea is just the beginning of Moscow's ambitions. Steve Rosenberg reflects on how this latest election has emboldened the President but there are voices of opposition willing to take a stand in spite of the consequences.When German Chancellor Olaf Scholz pledged the country was seeing a paradigm shift, or Zeitenwende, in supporting Ukraine in the war against Russia, he did not foresee how this would divide public opinion over Germany's potential involvement in a military campaign. Damien McGuinness reports on the ongoing political rifts in Berlin.Timor Leste has had a troubled history and faces multiple economic and social challenges including malnutrition and rural poverty. But marine scientists are discovering that Timor Leste lies on a vast migration route for a wide range of ocean wildlife, which some hope could fuel a fledgling tourism industry, reports Michelle Jana Chan.And we're in Oman, where a journey to the medieval capital of Nizwa leads to a conversation about the changes for women in the country, with a female driving instructor. Women have been legally allowed to drive in the country for more than 2 decades, unlike its neighbour Saudi Arabia, and a rise in the number of women in the workplace means more women are getting behind the wheel, says Sara Wheeler.Series Producer: Serena Tarling Editor: Richard Fenton-Smith Production Coordinator: Katie Morrison

President Putin has claimed a landslide victory in an election that featured no genuine competition. The last day of voting was marked by silent protests at polling stations. But how does his expected victory matter? And what might securing a fifth term mean for the war in Ukraine? Lyse and Vitaly are joined by the BBC's Russia editor Steve Rosenberg.Today's episode is presented by Lyse Doucet and Vitaly Shevchenko. The producer was Arsenii Sokolov. The technical producer was Rohan Madison. The series producer is Tim Walklate. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Kate Adie introduces dispatches from Ukraine, Russia, the USA and Georgia.Sarah Rainsford was in Ukraine when Vladimir Putin first launched his full-scale invasion two years ago, reporting on the defiance and rush to defend the country. On a recent trip back to the border city of Kharkiv, she found a much more sombre mood.Steve Rosenberg reflects on how the death of Russian opposition leader Alexei Navalny, along with two years of war with Ukraine, has affected the outlook of many ordinary Russians. Many wish for change, but are unclear on how that can be achieved.Over recent months, the stalled passage of a $60bn military aid package through the US Congress has heightened concerns that Washington's support for Ukraine is on the wane. Anthony Zurcher reflects on how the current US position has changed since his trip to Kyiv in the weeks before the Russian invasion began.Georgia has become a prime destination for Russians fleeing the war with Ukraine, especially those escaping conscription. The sudden arrival of tens of thousands of Russians has proved overwhelming at times, and given Georgia's own past conflict with Russia, not everyone is happy to see them, reports Vitaliy Shevchenko.Since Russia's invasion, more than 6 million Ukrainians have sought refuge overseas – but many people have stayed put, often by choice, determined to carry on living their lives as they have always done. Caroline Eden meets some market traders in Ukraine's southern port of Odessa, who are trying to ensure it's business as usual.Series Producer: Serena Tarling Production coordinator: Katie Morrison Editor: Richard Fenton-Smith

Saturday marks exactly two years of this conflict. On today's special episode, recorded in collaboration with the Global News Podcast, BBC experts from across the world answer YOUR questions on the war.Today's episode is presented by Oliver Conway and Vitaly Shevchenko, with the BBC's chief international correspondent, Lyse Doucet, in Kyiv, Russia editor Steve Rosenberg in Moscow and BBC Verify's Olga Robinson. It was made in collaboration with the Global News Podcast team. The producers were Keiligh Baker, Cordelia Hemming and Ivana Davidovic. The technical producer was Mike Regaard. The series producer is Lucy Boast. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Two years on from the start of the full-scale Russian invasion of Ukraine, the BBC's Russia editor, Steve Rosenberg, has been asking Russians what they think of the war. Also in the programme: Albania gives the green light to a controversial migrant processing centre - on behalf of Italy; and a court ruling in the US state of Alabama is enough to shut down some IVF treatment - as physicians run scared of being sued.(Photo: A mural of fallen Russian soldiers in Solnechnogorsk. Credit: BBC)

On this week's episode of the EcoNews Report, host Alicia Hamann from Friends of the Eel River is joined by long-time Eureka resident and fisherman Steve Rosenberg and Humboldt Trails Council's Advisory Chair Karen Underwood. Alicia and her guests reflect on the history of losing public access to rivers and wild spaces, and discuss modern efforts underway to protect what remains. Featured is the recent issue of attempts to limit access to one of the few remaining fishing access points along the Van Duzen River at Fisher Road.To learn more about this issue, please visit this link.Support the show

What's it like living in the Russian city under attack?We hear from a man in Belgorod, the Russian border city that Ukraine is targeting with missiles.Twenty-five people were killed and more than 100 others hurt there on 30 December, in what was one of the deadliest attacks on Russia since the full scale invasion. Missiles continue to be fired.Russia editor Steve Rosenberg is on to tell us how Russians are reacting, and what it means for the future of the war.Today's episode is presented by Victoria Derbyshire and Vitaly Shevchenko. It was made by Chris Flynn. The producers were Cordelia Hemming, Ivana Davidovic, Ben Tavener and Clare Williamson. The technical producers were Jack Graysmark and Philip Bull. The series producer is Lucy Boast. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480.You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord.

As the war in Ukraine approaches its second anniversary, what does 2024 hold for the conflict?BBC correspondents from across the world join us for a one-off special, looking at how elections in the UK, US and Russia will affect funding and the frontline.Europe editor Katya Adler, Russia editor Steve Rosenberg, Ukraine correspondent James Waterhouse and US State Department correspondent Barbara Plett Usher join us to answer your questions.Today's episode is presented by Lucy Hockings. The producers were Keiligh Baker, Clare Williamson, Arsenii Sokolov and Ivana Davidovic. The technical producer was Mike Regaard. The series producer is Lucy Boast. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

President Putin has held his first televised news conference since the full-scale invasion of Ukraine began in February 2022. Russia editor Steve Rosenberg gives his verdict on the annual show.And after a long night of intense talks, Ukraine is one step closer to joining the European Union - although long-term Putin ally Viktor Orban, of Hungary, vetoed a €50bn aid package to Kyiv. Europe correspondent Sofia Bettiza, who was at the summit in Brussels, explains what happened.Today's episode is presented by Victoria Derbyshire and Vitaly Shevchenko. It was made by Keiligh Baker and the producers were Arsenii Sokolov and Ivana Davidovic. The technical producer was Mike Regaard. The series producer is Lucy Boast. The senior news editor is Sam Bonham. Email Ukrainecast@bbc.co.uk with your questions and comments. You can also send us a message or voice note via WhatsApp, Signal or Telegram to +44 330 1239480You can join the Ukrainecast discussion on Newscast's Discord server here: tinyurl.com/ukrainecastdiscord

Kate Adie presents stories from Russia, the US, Argentina, Iraq and Iceland. In the wake of President Putin's invasion of Ukraine, repressive laws were passed which effectively criminalise all anti-war activism. The recent trial of artist Sasha Skochilenko underscored the heavy-handed enforcement of these laws, as well as the inconsistent way in which justice is applied in Russia. Steve Rosenberg was in St Petersburg. Democratic and Republican states are introducing radically different laws on issues ranging from LGBTQ rights to the teaching of black history. As a result, people on either side of the political divide are on the move – as they flee from one state to another more aligned with their politics. Lucy Proctor was in Chicago and Miami. Argentina has elected far-right outsider Javier Milei as President, bringing an end to an era that has largely been dominated by left-leaning ‘Peronist' parties. Mr Milei has pledged big spending cuts and low taxes alongside other more radical policies. Natalio Cosoy was in Buenos Aires to find out why voters backed Mr Milei. While armed violence in Iraq has ebbed in recent years, hundreds of people are still dying in accidents caused by poorly enforced safety standards as the country struggles to recover from years of war. For Iraqis who have lived through decades of conflict, these incidents represent another awful failure, says Lizzie Porter. In Iceland, residents of the fishing town of Grindavik have all been evacuated owing to warnings of an imminent volcanic eruption. Jessica Parker met locals recovering their belongings and saw the impact of the recent earthquakes first hand. Series Producer: Serena Tarling Production Coordinator: Gemma Ashman Editor: Richard Fenton-Smith