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In this episode of the Dr. Geo Prostate Podcast, Dr. Geo welcomes Dr. Alberto Vargas, Vice Chair of Oncologic Imaging at NYU Langone Health and expert in prostate cancer imaging.They dive deep into the evolving world of diagnostic tools—MRI, PET, CT, and PSMA scans—and how these technologies help detect, monitor, and guide treatment for prostate cancer. Dr. Vargas explains the difference between imaging modalities, when to use them, and how PSMA PET scans are changing the game in identifying recurrent and metastatic disease earlier than ever before.Key topics covered:MRI vs. PET vs. CT: what each scan shows and when it matters mostThe rise of PSMA PET for finding prostate cancer at extremely low PSA levelsWhy not all PET scans are the same, and how tracers like FDG, Axumin, and PSMA workThe potential future of prostate cancer diagnosis: fewer biopsies, more imagingLimitations, false positives, and how imaging results are interpretedThe role of imaging in both first-time diagnosis and recurrenceWhether you're a patient, caregiver, or clinician, this episode offers valuable insight into how imaging helps guide smart, proactive decisions in prostate cancer care.----------------Thank you to our partnersThe ProLon 5-Day Fasting Mimicking Diet is a plant-based meal program designed to provide fasting benefits while allowing food intake. Developed by Dr. Valter Longo, it supports cellular renewal, fat loss, and metabolic health through low-calorie, pre-packaged meals that maintain the body in a fasting state.Special Offer: Thank you for listening, you can purchase the ProLon kit for just $148 by using this link.We'd also like to thank our partner AG1 by Athletic Greens. AG1 contains 75 high-quality vitamins, minerals, whole-food sourced ingredients, probiotics, and adaptogens to help you start your day right. This special blend of ingredients supports your gut health, nervous system, immune system, energy, recovery, focus, and aging. All the essentials in one scoop. Enjoy AG1 by Athletic Greens.----------------Thanks for listening to this week's episode. Subscribe to The Dr. Geo YouTube Channel to get more content like this and learn how you can live better with age.You can also listen to this episode and future episodes of the Dr. Geo Podcast by clicking HERE.----------------Follow Dr. Geo on social media. Facebook, Instagram Click here to become a member of Dr. Geo's Health Community.Improve your urological health with Dr. Geo's formulated supplement lines:XY Wellness for Prostate cancer lifestyle and nutrition: Mr. Happy Nutraceutical Supplements for prostate health and male optimal living.You can also check out Dr. Geo's online dispensary for other supplement recommendations Dr. Geo's Supplement...
In this episode of the Dr. Geo Prostate Podcast, Dr. Geo welcomes Dr. Alberto Vargas, Vice Chair of Oncologic Imaging at NYU Langone Health and expert in prostate cancer imaging.They dive deep into the evolving world of diagnostic tools—MRI, PET, CT, and PSMA scans—and how these technologies help detect, monitor, and guide treatment for prostate cancer. Dr. Vargas explains the difference between imaging modalities, when to use them, and how PSMA PET scans are changing the game in identifying recurrent and metastatic disease earlier than ever before.Key topics covered:MRI vs. PET vs. CT: what each scan shows and when it matters mostThe rise of PSMA PET for finding prostate cancer at extremely low PSA levelsWhy not all PET scans are the same, and how tracers like FDG, Axumin, and PSMA workThe potential future of prostate cancer diagnosis: fewer biopsies, more imagingLimitations, false positives, and how imaging results are interpretedThe role of imaging in both first-time diagnosis and recurrenceWhether you're a patient, caregiver, or clinician, this episode offers valuable insight into how imaging helps guide smart, proactive decisions in prostate cancer care.----------------Thank you to our partnersThe ProLon 5-Day Fasting Mimicking Diet is a plant-based meal program designed to provide fasting benefits while allowing food intake. Developed by Dr. Valter Longo, it supports cellular renewal, fat loss, and metabolic health through low-calorie, pre-packaged meals that maintain the body in a fasting state.Special Offer: Thank you for listening, you can purchase the ProLon kit for just $148 by using this link.We'd also like to thank our partner AG1 by Athletic Greens. AG1 contains 75 high-quality vitamins, minerals, whole-food sourced ingredients, probiotics, and adaptogens to help you start your day right. This special blend of ingredients supports your gut health, nervous system, immune system, energy, recovery, focus, and aging. All the essentials in one scoop. Enjoy AG1 by Athletic Greens.----------------Thanks for listening to this week's episode. Subscribe to The Dr. Geo YouTube Channel to get more content like this and learn how you can live better with age.You can also listen to this episode and future episodes of the Dr. Geo Podcast by clicking HERE.----------------Follow Dr. Geo on social media. Facebook, Instagram Click here to become a member of Dr. Geo's Health Community.Improve your urological health with Dr. Geo's formulated supplement lines:XY Wellness for Prostate cancer lifestyle and nutrition: Mr. Happy Nutraceutical Supplements for prostate health and male optimal living.You can also check out Dr. Geo's online dispensary for other supplement recommendations
En 2010, certains éditeurs cherchent encore à se faire une place au soleil des AAA en mettant de plus gros moyens dans de nouvelles licences. C'est le cas de THQ, qui mise sur le studio Vigil Games et son premier jeu : Darksiders. Mené par Joe Madureira, le projet vient se frotter à Kratos et Link, en proposant un jeu d'aventure rythmé par des combats sanglants et des puzzles plus ou moins pesants. Efficace, bien habillé par sa reprise des 4 cavaliers de l'apocalypse, il convainc largement à l'époque. Malheureusement, la licence connaitra un destin chaotique, prise dans les déconvenues de son éditeur. FDG profite de l'aventure de Guerre pour revenir sur la chute de THQ.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkNSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAME pour soutenir l'émission Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.
Vampire Survivors est de ces jeux qu'on n'a pas vus venir mais qu'on voit partout depuis. Développé d'abord comme un projet de framework, son créateur, Poncle, s'est tellement amusé dessus qu'il a fini par le sortir en tant que jeu solo. Et s'il aura fallu quelques vidéos de Youtubers célèbres pour lancer la vague, elle ne s'est jamais calmée. Sa formule qui consiste à enchainer les récompenses et les choix pour maximiser ses DPS n'a besoin que de quelques minutes pour démontrer son efficacité et accrocher le chaland. Et ses multiples défis sont là pour nous engager sur la durée. A moins de se porter sur un de ses nombreux clones, qui profitent des faiblesses assez évidentes du titre pour se tailler une part du gâteau. Retour sur la recette originale (ou presque) dans cet épisode de FDG.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkNSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAME pour soutenir l'émission. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.
Dans cet épisode, l'escouade de FDG plonge dans Helldivers 2, l'immense succès populaire du début de l'année 2024. Un deuxième opus qui reprend texto la formule du jeu d'origine sorti 10 ans plus tôt, mais en la transposant dans un TPS moderne. Il s'agit toujours de massacrer des bestioles et autres automatons sur l'autel de la Liberté, en évitant au possible les pertes alliées dues à des obus plus ou moins perdus. Un jeu pensé pour la coopération et le grind, qui brille moins par sa profondeur que par son sens du burlesque et de la pyrotechnie. Ce n'est pas la grande satire qu'on a pu faire de lui, mais le meilleur simulateur de stormtrooper ? Probablement.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkNSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAME pour soutenir l'émission. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.
Après la sortie compliquée du premier Alan Wake, il aura fallu 13 ans pour que Remedy remonte sa licence à la surface. La recette reste la même : un TPS classique pris entre le surnaturel et l'horreur psychologique. Mais cette suite va bien plus loin formellement, en usant (et abusant) de très nombreuses séquences filmées, des pubs, des concerts, des vlogs et autres superpositions d'images pour narrer son histoire. Le tout convoquant des références incessantes, à Lynch comme aux précédents titres du studio. Un méli-mélo qui peut rendre le titre attachant mais qui embourbe son gameplay déjà convenu dans un rythme laborieux et laisse finalement peu de place à celle ou celui qui tient la manette. Et qui en donne beaucoup, beaucoup à Sam Lake. FDG revient sur cet égo-trip à l'équilibre bien précaire.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkNSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAME pour soutenir l'émission. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.
Avant de passer en 2025, le trio de FDG remonte dans le temps de 30 années pour revenir sur Chrono Trigger. Un jeu qui tenait presque du fantasme à l'époque de sa sortie, puisqu'il réunissait les créateurs de Final Fantasy, Dragon Quest et Dragon Ball. Une “dream team” qui a donné vie à un J-RPG ambitieux et avant-gardiste, par sa structure construite autour du voyage dans le temps, son rythme ou son traitement des combats, intégrés directement dans l'espace de jeu. Une grande épopée à travers le temps qui nous mettait face aux conséquences de nos choix, et ce, même après l'avoir terminé une première fois. Pas étonnant qu'il soit devenu culte, et même considéré encore aujourd'hui comme un des meilleurs représentants de son genre. Une bien belle façon de terminer l'année.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkNSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAME pour soutenir l'émission. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.
Sometimes, fluctuating disabilities mean you have to pivot plans, and that's okay x 00:00 – Intro 03:52 – Arevya played Super Market Simulator, Botany Manor 05:30 – Steven Spohn and Mark Barlet are leaving AbleGamers 08:40 – FDG 2025 will have the theme "Accessible Worlds, United Through Play" 10:35 – Laura and Arevya have consulted on Sorry, We're Closed 12:05 – Arevya consulted on Life Below 14:43 – Lauras take on the PS5 PRO 19:15 – Laura has played Mario & Luigi Brothership, Super Mario Party Jamboree, Dragon Age: The Veilguard, and LEGO Horizon Adventures 36:25 – Where to find us
In today's episode, we delve into the world of PET scans and other imaging modalities crucial for accurate diagnosis and staging of breast cancer. We are joined by two incredible guests: Dr. Kiser, the Medical Director of Molecular Imaging for Carilion Clinic, and Pam Kohl, a patient advocate living with metastatic breast cancer.Dr. Kiser provides an in-depth explanation of PET scans, particularly focusing on FDG and FES (also known as Cerianna) PET scans. FDG-PET scans use radioactive glucose to highlight cancerous tissues, while FES-PET scans target estrogen receptors, making them highly specific for ER-positive breast cancer. Dr. Kiser emphasizes the revolutionary impact of these imaging techniques in both diagnostics and therapeutics.Pam shares her personal experience with breast cancer, highlighting the importance of advocating for oneself. Diagnosed with early-stage breast cancer in 2009, Pam experienced a recurrence in 2017, which led to a stage 4 metastatic diagnosis. Her story underscores the critical role of PET scans in detecting metastasis early and informing effective treatment plans. Pam's experience with FES-PET scans has been particularly transformative, allowing her medical team to tailor her treatment precisely to her cancer's characteristics.SURVIVINGBREASTCANCER.ORGAttend a free virtual SurvivingBreastCancer.org event:https://www.survivingbreastcancer.org/eventsFollow us on InstagramSurvivingBreastCancer.org: https://www.survivingbreastcancer.org/Breast Cancer Conversations: https://www.instagram.com/breastcancerconversations/About SurvivingBreastCancer.org: SurvivingBreastCancer.org, Inc. (SBC) is a federally recognized 501(c)(3) non-profit virtual platform headquartered in Boston with a national and global reach. Through education, community, and resources, SurvivingBreastCancer.org supports women and men going through breast cancer. We provide a sanctuary of strength, compassion, and empowerment, where those diagnosed with cancer unite to share their stories, learn invaluable coping strategies to manage wellness and mental health, and find solace in the unbreakable bond that fuels hope, resilience, and the courage to conquer adversity.Support the Show.
A new study finds insulin resistance and reduced glucose uptake in the heart is linked with early-onset atherosclerosis and heart issues. Sponsored: Support your Workout Sessions and Healthy Hydration with the Electrolyte + Creatine Combo by MYOXCIENCE: https://bit.ly/electrolyte-stix *Save 12% with code podcast at checkout Link to Video and Research: https://bit.ly/3UXLhal Research Mentioned: Devesa, A. et al. Cardiac Insulin Resistance in Subjects With Metabolic Syndrome Traits and Early Subclinical Atherosclerosis. Diabetes Care 46, 2050–2057 (2023). Time Stamps: 00:00 FDG = Fluorodeoxyglucose 00:30 Reduced glucose uptake in the heart is tethered to atherosclerosis. 01:20 LDL levels are not strongly associated with poor outcomes. 02:00 Your heart becomes insulin resistant. 03:05 Those with no glucose uptake in the heart had higher fasting glucose. 03:45 Those with more cardiovascular risk factors had lower LDL. 04:35 The heart can generate energy from fatty acids, carbs, and ketones. 05:00 Cardiac abnormalities are associated with metabolic syndrome. 07:00 Insulin resistance changes muscle and heart muscle. 09:16 Insulin resistance is associated with a progressive decrease of myocardial FDG uptake. 09:50 Cardiovascular risk increases with the decline of FDG uptake. 11:30 Your heart loses the ability to pump blood effectively as it loses ability to utilize different energy substrates. 12:40 Support your heart by supporting your metabolism.
Help us with a DONATION You can support and help the FDG With TC Dj (Live) Help us with a DONATION You can support and help the FDG by making a donation via bank transfer to the following coordinates: UNICREDIT Bank IT 87 S 02008 44101 000004613369 Reason: "donation to help young diabetics". Aiutaci con una DONAZIONE Puoi sostenere e aiutare la FDG facendo una donazione tramite bonifico bancario alle seguenti coordinate: Banca UNICREDIT IT 87 S 02008 44101 000004613369 Causale: “donazione per aiuto ai giovani diabetici”. https://www.fdgdiabete.it/
This audio is brought to you by Endress and Hauser, a leading supplier of products, solutions and services for industrial process measurement and automation. State-owned electricity utility Eskom will reduce planned maintenance to 3 000 MW during the upcoming winter season and will seek to keep unplanned breakdowns to below 14 000 MW in a bid to navigate the high-demand period with limited loadshedding. During the summer period, from September to the end of March, the utility set a target of restricting unplanned breakdowns to 14 500 MW during the high-maintenance summer months, when average planned maintenance levels of 7 000 MW were targeted. During those periods when breakdowns exceeded the target, loadshedding was typically implemented, at times at high levels of intensity of between Stage 4 and 6. While the winter outlook was still being finalised, Eskom Generation's Eric Shunmagum confirmed during a briefing on the implementation of the Energy Action Plan that it should be released later this month. He also confirmed that the diesel budget for the 2024/25 financial year would be below the R30-billion set aside for the operation of the Eskom and independent power producer open-cycle gas turbines in 2023/24; a budget that he confirmed had been marginally exceeded, without providing specifics. The diesel budget for the current financial year, meanwhile, would be communicated at a future briefing. Speaking amid a sustained period during which Eskom had not resorted to loadshedding, Shunmagum stressed that the winter plan, as with previous plans, would contain three scenarios, with the base scenario likely to indicate only limited loadshedding for the period from April to the end of August. He also insisted that Eskom Generation would work to ensure that breakdowns were kept below the 14 000 MW level to further reduce the threat of loadshedding. However, the coal fleet remained unreliable with intense recovery work still under way at six priority stations, including Majuba, Matla, Duvha, Kendal, Tutuka and Kriel, which had replaced Kusile on the list after Kusile's performance was deemed to have recovered following the introduction of temporary stacks. EAF TARGET MISSED Meanwhile, Electricity Minister Kgosientsho Ramokgopa confirmed that the Eskom fleet failed to achieve the 65% energy availability factor (EAF) target set by the board for the end of March, coming in at only 54.6%. The performance was even below the 56% EAF reported by Eskom in its previous financial year. Nevertheless, Shunmagum described the target as non-negotiable and insisted that the 65% to 70% target remained intact for the current financial year. Ramokgopa attributed the failure to achieve the EAF target to "aggressive planned maintenance" efforts, which he said were prioritised ahead of lifting the EAF to closer to 60%. "Planned maintenance increased from 9.3% in FY2023 to 12.0% in FY2024 reinforcing the commitment to execute the recovery plans and reduce plant risks," he said. The Minister also insisted that various additional capacity was scheduled to be added or returned to service over the coming five months, including: Medupi Unit 4 in August, where a second-hand generator was being installed after a unit was crippled by a fire incident in August 2021; Koeberg Unit 2, which is currently scheduled to return from an extended outage in September; and Kusile Unit 6, which is also currently scheduled to be synchronised to the grid in September. "In the next five months, we should be able to get 2 583 MW of new generation capacity [from Eskom]," Ramokgopa said. He also played down concerns that up to 2 100 MW of Kusile capacity would be unavailable from November, when the three units that are currently bypassing the flue-gas desulphurisation (FGD) plant using temporary stacks, were scheduled to start being reconnected to the FDG through the west stack. The west stack was rendered inoperable when Kusile's Unit 1 flue duct collapsed because of an unco...
This audio is brought to you by Endress and Hauser, a leading supplier of products, solutions and services for industrial process measurement and automation. State-owned electricity utility Eskom will reduce planned maintenance to 3 000 MW during the upcoming winter season and will seek to keep unplanned breakdowns to below 14 000 MW in a bid to navigate the high-demand period with limited loadshedding. During the summer period, from September to the end of March, the utility set a target of restricting unplanned breakdowns to 14 500 MW during the high-maintenance summer months, when average planned maintenance levels of 7 000 MW were targeted. During those periods when breakdowns exceeded the target, loadshedding was typically implemented, at times at high levels of intensity of between Stage 4 and 6. While the winter outlook was still being finalised, Eskom Generation's Eric Shunmagum confirmed during a briefing on the implementation of the Energy Action Plan that it should be released later this month. He also confirmed that the diesel budget for the 2024/25 financial year would be below the R30-billion set aside for the operation of the Eskom and independent power producer open-cycle gas turbines in 2023/24; a budget that he confirmed had been marginally exceeded, without providing specifics. The diesel budget for the current financial year, meanwhile, would be communicated at a future briefing. Speaking amid a sustained period during which Eskom had not resorted to loadshedding, Shunmagum stressed that the winter plan, as with previous plans, would contain three scenarios, with the base scenario likely to indicate only limited loadshedding for the period from April to the end of August. He also insisted that Eskom Generation would work to ensure that breakdowns were kept below the 14 000 MW level to further reduce the threat of loadshedding. However, the coal fleet remained unreliable with intense recovery work still under way at six priority stations, including Majuba, Matla, Duvha, Kendal, Tutuka and Kriel, which had replaced Kusile on the list after Kusile's performance was deemed to have recovered following the introduction of temporary stacks. EAF TARGET MISSED Meanwhile, Electricity Minister Kgosientsho Ramokgopa confirmed that the Eskom fleet failed to achieve the 65% energy availability factor (EAF) target set by the board for the end of March, coming in at only 54.6%. The performance was even below the 56% EAF reported by Eskom in its previous financial year. Nevertheless, Shunmagum described the target as non-negotiable and insisted that the 65% to 70% target remained intact for the current financial year. Ramokgopa attributed the failure to achieve the EAF target to "aggressive planned maintenance" efforts, which he said were prioritised ahead of lifting the EAF to closer to 60%. "Planned maintenance increased from 9.3% in FY2023 to 12.0% in FY2024 reinforcing the commitment to execute the recovery plans and reduce plant risks," he said. The Minister also insisted that various additional capacity was scheduled to be added or returned to service over the coming five months, including: Medupi Unit 4 in August, where a second-hand generator was being installed after a unit was crippled by a fire incident in August 2021; Koeberg Unit 2, which is currently scheduled to return from an extended outage in September; and Kusile Unit 6, which is also currently scheduled to be synchronised to the grid in September. "In the next five months, we should be able to get 2 583 MW of new generation capacity [from Eskom]," Ramokgopa said. He also played down concerns that up to 2 100 MW of Kusile capacity would be unavailable from November, when the three units that are currently bypassing the flue-gas desulphurisation (FGD) plant using temporary stacks, were scheduled to start being reconnected to the FDG through the west stack. The west stack was rendered inoperable when Kusile's Unit 1 flue duct collapsed because of an unco...
À la fin des années 2000, le cover shooter domine le jeu vidéo mainstream et son roi s'appelle Gears Of War 2. Après un premier épisode qui a posé toutes les bases, cette suite vient parfaire la formule conçue par Cliff Blezinski et les équipes d'Epic Games. Un shooter pensé pour une console grand public, où on prend ses positions, on vide ses chargeurs et on tronçonne du locuste en lâchant de punchlines plus ou moins élégantes. Et si ça paraît un peu désuet aujourd'hui, ce Gears 2 nous rappelle que ça ne fait pas si longtemps que les gros jeux s'appuient sur différents piliers de gameplay pour se renouveler. FDG revient sur l'Epic Games pré-Fortnite, mais bien pro-Lanzor.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAMERejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkN
En à peine 2 opus, la série Little Nightmares s'est déjà imposée comme une référence dans le genre "jeu d'aventure court, abordable et spooky". Bon. C'est vrai que la catégorie n'est pas encore bien chargée mais c'est aussi que les jeux du studio Tarsier proposent une formule calibrée, entre des puzzles légers, des séquences de cache-cache avec des monstres maladroits mais bien affreux et des courses-poursuites qui font monter l'adrénaline. Le tout dans des décors qui viennent chercher le petit gosse apeuré qui sommeille en chacun et chacune de nous. Et si ça reste perfectible, sur les mécaniques comme sur la narration, on ne peut nier l'efficacité de ces petits contes vidéo-ludiques macabres, surtout quand on voit leurs chiffres de ventes. On attend maintenant de voir la suite pour Tarsier, et comment Bandai Namco va exploiter la licence à l'avenir. L'équipe FDG sort son plus beau k-way jaune et s'engouffre dans ces petits cauchemars.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameSi vous réalisez un achat sur Top Achat, vous pouvez entrer le code créateur FINDUGAMERejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkN
Soluce, c'est le nouveau podcast JV co-créé par Hugo de la team FDG et Lucie Ronfaut, journaliste spécialisée dans les nouvelles technologies. C'est une mini-série de 5 épisodes, qui tente de replacer le Jeu Vidéo au sein de nos vie quotidiennes. C'est dispo partout et si vous aimez FDG, allez écouter ça ! https://shows.acast.com/soluce
Drs. Diwakar Davar and Ben Boursi discuss the role of the gut microbiome in the outcome of cancer immunotherapy and the prevention of immunotherapy-related adverse events, as well as compelling research on nutritional interventions to improve response to immune checkpoint inhibitors. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm 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. Researchers have shown that microorganisms in the gut can impact the effectiveness of immunogenic chemotherapy for patients with cancer. Although microbial therapies for cancer are still at a very early stage of clinical development, compelling research in recent years has shown that changing the gut microbiome can help improve outcomes in patients receiving treatments for cancer enduring immune checkpoint inhibition. My guest today is Dr. Ben Boursi, a GI medical oncologist at the Sheba Medical Center at Tel Aviv University in Israel. Dr. Boursi is also an adjunct professor at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He joins me today to discuss his pivotal research on the role of the gut microbiome in mediating its effects on immunotherapy. And again, I want to highlight that we're recording this on October 9th, and as you may well know, many recent events over the last couple of days have happened in Israel, and so Dr. Boursi has joined us at a very difficult time. So, we're very grateful for him taking time out of his suddenly very busy schedule to join us at a time that is fraught for all. You'll find our disclosures in the transcript of this episode. You'll also find the disclosures of all guests on the podcast at asco.org/DNpod. Ben, it's great to have you on the podcast today. Thank you for being here at such a difficult time, sharing what will, I think, be a great episode. Dr. Ben Boursi: Thanks for having me, Diwakar. Dr. Diwakar Davar: Ben, the gut microbiome and its role in terms of mediating effects and side effects of cancer immunotherapy has gotten a lot of interest recently. You've done some fundamental work in this space. Why don't you briefly summarize for the audience, firstly, what is the gut microbiome and what are the major themes in relation to cancer immunotherapy? Dr. Ben Boursi: Well, the microbiome is the ecosystem of microorganisms, bacteria, phages, fungi, that are crucial for immunologic, metabolic and hormonal homeostasis of the host. In the last decade, we began to understand the central role of the gut and tumor microbiome in tumorigenesis, metastasis, treatment efficacy and toxicities, and in 2022, polymorphic microbiomes became one of the hallmarks of cancer, in addition to previous hallmarks that focused mainly at the cellular/genetic levels. The initial studies in mice models showed that therapeutic efficacy of immunotherapy depends on both the presence and composition of the microbiota (In germ-free or antibiotic treated mice, immunotherapy is ineffective), and following these studies, three observational studies in human patients showed that the gut microbiome can predict response to immunotherapy and that response to immunotherapy could be transferred to germ-free mice by fecal microbiota transplantation (FMT) from responding patients. These studies helped us to define three main research questions regarding the possible role of microbial modulation in cancer treatment. First, can microbial modulation overcome resistance to immunotherapy, both primary and secondary resistance? And this question was the focus of the initial proof of concept studies. Second, can microbial modulation improve response to immunotherapy in treatment-naive patients? And third, can microbial modulation prevent or treat immune related adverse events? The initial positive results of clinical trials also led to additional questions. For example, can microbial modulation induce anti-tumor immune response even in non-immunogenic tumors? And it is important to note that there are many ways to modulate the microbiota, but so far, the only reliable way that showed positive results is fecal microbiota transplantation that allows the transfer of the entire microbiota both in terms of composition and relative abundance. Dr. Diwakar Davar: That's great. Essentially with the trials that I think the data sets that you're referencing of course, are papers by Jennifer Wargo, Thomas Gajewski, and Lawrence Zitvogel, looking at the role of gut microbiota in several different cancers, primarily immune checkpoint sensitive tumors such as melanoma, non-small cell lung cancer and kidney cancer. And then the work from several different groups showing that essentially proof of concept experiments can be done to try to change this, certainly preclinically, and now we know that that can be done clinically. So, I guess the failure rates of immunotherapy in some patients are quite high. And we know that the microbial composition can change the likelihood to respond to immunotherapy based on all these trials. And actually, even going back to 2015, we had two seminal papers that looked at the role of CTLA-4 blockade as well. But subsequently, many years after that, 7 years after 2015, and certainly 3 years after 2018, when the three observational PD-1 papers were published, there were 2 pivotal trials in PD-1 advanced or refractory melanoma. They demonstrated that changing the gut microbiome can reprogram the immune system to attack tumors. So, there were 2 separate trials, both published the same issue of Science. One trial was led by your group at Sheba, and another one's led by us, the University of Pittsburgh. Why don't you summarize both studies for our audience. Dr. Ben Boursi: So, both studies were Phase I clinical trials of FMT in metastatic melanoma patients who failed immunotherapy. Recipients were metastatic melanoma patients that progressed on at least one line of anti PD-1 and in BRAF mutated patients, BRAF inhibitors as well. Donors in the Sheba study were metastatic melanoma patients with durable complete responses to immunotherapy for at least one year, and in the Pittsburgh study, you also included patients with durable partial responses of more than two years as donors. It is important to note that each fecal transplant in both studies was composed of a single donor. Prior to transplantation, we performed a microbiome depletion phase using a combination of two antibiotics, vancomycin and neomycin. The goal of this phase was to assist in engraftment (by avoiding colonization-resistance by recipient bacteria) and to “reset” the immune system, which may remind some people of the logic behind bone marrow transplantation. In the Pittsburgh study, there was no bacterial eradication with antibiotics, mainly because of studies showing that response to immunotherapy is lower following antibiotic treatment. Both studies performed FMT through colonoscopy. At Sheba, we also performed maintenance FMT using capsules in order to keep the donor's microbial composition. After the initial FMT, both studies reintroduced the same immunotherapy in which the patient progressed in the past. Clinically, we have seen a 30% response rate with durable, complete and partial responses, and in the Pittsburgh study, there was a 20% response rate and 40% disease control rate. Both studies showed following FMT, immune response in the gut and in the tumor, and tumors that were immune deserts prior to FMT became infiltrated with lymphocytes. Interestingly, in our study, there were no moderate to severe immune related adverse events following FMT and reintroduction of immunotherapy. And this is despite the fact that five of the patients had significant side effects during previous rounds of the same immunotherapy. Dr. Diwakar Davar: So essentially, in these very early proof of concept studies, what I think is pretty remarkable is that obviously the sample sizes were very small, but remarkably, patients that appeared to respond, responded in a setting in which they were not expected to respond. So, the probability of a patient responding to attempt at giving PD-1 in patients who were PD-1 relapse refractory is on the order of about 7%, based on an FDA analysis by Viva et al. And here, two separate studies, two independent studies, investigators had not known that each paper was being published, remarkably similar results clearly demonstrating that this is perhaps one of the best pieces of evidence to suggest that microbiome modulation may actually truly be effective in reversing PD-1 refractoriness. More recently, our colleague Dr. Bertrand Routy at University of Montreal has done a proof of concept trial in evaluating the use of healthy donor fecal microbiota transplant in addition to anti PD-1 monotherapy in PD-1 naive metastatic melanoma. In this study, published in Nature Medicine a few weeks ago, his group reported an objective response rate of 65%. What are your thoughts about this study? And specifically, what are your thoughts about some of the pharmacodynamic and translational results that were demonstrated? Dr. Ben Boursi: This is a very interesting question, because in both the Sheba and the University of Pittsburgh studies we chose responding patients as donors. We thought that by using these patients, we provide beneficial bacteria that enhance responses to immunotherapy through several mechanisms (molecular mimicry, immunomodulatory bacterial metabolites, modulation of immune checkpoint expression, and much more), and here in the Routy paper, the researchers used FMT from healthy donors without any selection for specific beneficial bacteria, and they demonstrated a similar effect on overall response rate. So maybe FMT works actually through reducing colonization by deleterious bacteria? Another question that we should ask is whether we need to choose donors differently when we use microbial modulation in treatment resistant patients compared to treatment-naive patients? Moreover, a previous meta-analysis of FMT studies across indications that was conducted by the group of Dr. Nicola Segata, demonstrated that recipients with better engraftment were more likely to experience clinical benefit, and that increased engraftment was mainly observed in individuals receiving FMTs through multiple routes, colonoscopy and capsules, as well as recipients that received antibiotics prior to FMT. But in Routy's trial, they not only used healthy donors, they performed bacterial cleansing only prior to FMT instead of bacterial eradication with antibiotics, and used FMTs through colonoscopy only, and they didn't give maintenance FMT. Of course, such an approach is much more feasible in the clinical setting and is relevant for designing future clinical trials. Dr. Diwakar Davar: So, many differences, relatively few similarities, but I guess one interesting point is that of engraftment, which is that in your paper, our paper, and certainly in Bertrand's paper, it is very interesting that engraftment appears to be a key pharmacodynamic biomarker of microbiome modulation. And certainly, the analogy that you used earlier, which is that it's very similar to what happens in a stem cell transplant, which is that if there's no take, there's probably not going to be any effect. So that's very interesting that engraftment is emerging as a key PD biomarker of essentially the success of any kind of microbiome modulation across multiple different settings. Now, we've heard of certainly defined microbial consortia, of cultivated species, as an alternative gut microbiome modulation strategy that balances the benefits of the ecological complexity of FMT with the scalability and practicality of probiotics. Do you think we are ready to design consortia? Dr. Ben Boursi: So to date there are several probiotics that use a single bacteria and several microbial consortia that were evaluated in clinical trials, and as you mentioned, they may offer more tractable solutions for widespread clinical use. If we begin with the single bacteria probiotics, two phase 2 clinical trials found that administration of the butyrate producing probiotic clostridium butyricum 588 (CBM588) to immunotherapy naive patients with metastatic renal cell carcinoma led to markedly better immunotherapy responses, although the probiotic had a minimal effect on the composition of the microbiota, and the control arm of the trial responded worse than expected. In addition, in preclinical studies, probiotic strains of lactobacillus and bifidobacterium have been shown to enhance immune control of transplanted tumors and to augment anti PD-1 activity. However, a clinical trial in patients with metastatic melanoma found that the use of lactobacillus or bifidobacterium probiotics was associated with reduced microbiota diversity and worse responses to anti PD-1. So here the conclusion is that when we try to design probiotics, we should not focus only on the composition since other factors, such as the relative abundance also matter. Too much of a beneficial bacterial species may potentially be worse than having a balanced and diverse microbiota. For example, a recent study of patients with non-small cell lung cancer receiving immunotherapy found that patients with a detectable Akkermansia muciniphila in their gut microbiota (this is a beneficial bacteria) responded well to treatment, but those with relative abundance of Akkermansia muciniphila greater than 5% responded worse than patients lacking Akkermansia, and this is due to the mucolytic effect of the bacteria. So, the use of rationally designed consortia may be better than a single probiotic strain. And there are currently 3 main microbial consortia that are being evaluated: the SER-401, a bacterial consortium enriched with clostridium, led in a randomized controlled trial to reduced response to immunotherapy compared to placebo control in first line metastatic melanoma patients, potentially due to a confounding effect of a vancomycin pretreatment; MET4 is a 30 bacteria consortium that was shown to be safe and to alter the gut microbiota and serum metabolome of immunotherapy naive patients. Here, the initial study was underpowered to determine the effect on treatment efficacy; And finally, VE800 is an immunotherapy enhancing 11-bacterial consortium that is currently being evaluated in phase 1 and 2 clinical trials, and we are looking forward to see the results with this agent. Dr. Diwakar Davar: So I guess where we are right now is that social design is clearly difficult because of all the reasons you've mentioned. The SER-401 data and the MET4-IO trials certainly give us pause for thought. Certainly, no pharmacodynamic changes that were seen with SER-401, MET4-IO did result in pharmacodynamic shifts metagenomically, but neither trial was positive. And certainly, the VE800 trial, which has been ongoing now for several years, and the lack of publicly reported data certainly doesn't suggest that there's a huge efficacy signal. So consortias, at least at this point, certainly do not appear to be having a significant effect, though we don't know what might happen in the future. Data from multiple groups has shown that gut microbial composition influences the development of immune related adverse events (irAEs) in both PD-1 and combination PD-1 and CTLA-4 treated patients. Unsurprisingly, as a result, there have been attempts made at evaluating the role of fecal microbiota transplants to treat refractory immune related adverse events and very specifically immune checkpoint associated colitis or IMC. So, Dr. Yinghong Wang, who is the chair of the Immunotherapy Toxicity Working Group at the University of Texas MD Anderson Cancer Center has been very prominent in this space, and in a recent paper published in Science Translational Medicine, which is a follow up paper to her early work in Nature Medicine, she reported that HDFMT, healthy donor fecal transplantation, was very efficacious in feeding early refractory immune checkpoint colitis. So, what are your thoughts on this approach and how important is this space and where else might it be efficacious? Dr. Ben Boursi: When I talked about the Sheba clinical study, I mentioned the possible role for microbiota modulation in the prevention of immunotherapy related adverse events in general, not only colitis. But the study by Dr. Yinghong showed that FMT can actually treat immune-related colitis refractory to steroids and anti-TNF. Now, this approach is probably relevant not only for immune related colitis, but also to other immune related adverse events. We can define certain bacterial species that may be associated with different immune related events. For example, streptococci can be associated with immune related arthritis. And maybe in the future we won't need to use FMT, but we will rather be able to target these specific immunogenic strains by narrow spectrum antibiotics or phages. The main challenge would be to develop microbiotic targeting interventions that reduce immune related adverse events without compromising therapeutic efficacy. Now, is microbial modulation relevant only for toxicity from immune checkpoint inhibitors? So, the answer is ‘no'. We know mainly from animal models of hematopoietic cell transplantation, CAR T, and immune agonist antibodies that antibiotic-treated or germ-free mice have markedly reduced immunotoxicity, such as graft versus host disease, cytokine release syndromes, and more. It is also worth mentioning that microbial modulation is relevant not only for reducing toxicity from immunotherapy, but also from chemotherapy and other anticancer modalities. And the best example is the gastrointestinal toxicity of irinotecan that is mediated by the bacterial beta-glucuronidase. And here the targeting may even be a bit less complex. Dr. Diwakar Davar: So, what we take away from that is that starting with actually your paper originally, and papers to be produced, immune-related adverse events can be prevented using microbiome modulation with FMT, and Dr. Wang's data suggesting that eventually FMT can be used to eradicate highly refractive colitis, again, this is important to keep in mind that this approach is not yet FDA-approved. It's being done under IND. It's not currently something that is a certain standard of care. One interesting area of drug development is that there's a French microbiome company named MaaT Pharma where they have an agent that is a very interestingly a pooled microbiome product from multiple different donors. Again, the trials in both Israel and Pittsburgh used individual donors. This is a pooled donor construct. The lead candidate is actually graft versus host disease. The trial is the ARES trial, A-R-E-S, as in the Roman god of war. This trial is actually ongoing in Europe, and I believe there's some effort to try to see whether or not it's going to be a trial that can be done in the United States as well. So, at this point in time, again, we don't know whether or not there are any developmental approaches from a pharmaceutical company in the United States, but certainly this is definitely an area of interest. So microbial therapies are still relatively early. It's going to be interesting to see how the advanced field of nutritional interventions provide an appealing method for modulating the gut microbiome due to the excellent safety profile, cost effectiveness and noninvasiveness. And certainly, if you are what you eat and your bacteria are what they eat, which goes down to our diet, there's enough rationale to believe that certain nutritional interventions can have an effect via the intermedial gut microbiota modulation. Holistic dietary changes and or supplementation specific nutrients such as prebiotics could therefore be utilized to specifically shape the population of beneficial microbes and shift the immune microbiota landscape. Now, we have seen in data published by several of our colleagues that in patients with cancer, high fiber intake is associated with greater microbial diversity, greater abundance in fiber fermenting microbes such as members of the Ruminococcaceae family, and these are all associated with the response to checkpoint inhibitor therapy. So, what do you think about nutritional interventions? Do you want us to briefly summarize data regarding nutritional data and where it stands in cancer at his time? And can you speculate as to how effective this might be in the context of patients with cancer? Dr. Ben Boursi: So, let's begin with diet. A growing number of clinical and preclinical studies suggest that specific dietary interventions such as a high fiber diet can not only improve response to immune checkpoint blockers, but also reduce immunotoxicity such as graft versus host disease. And there are many other diets that are being tested such as ketogenic diets and intermittent fasting. And the effects of diet may be mediated by both microbiota-dependent and microbiota-independent mechanisms. The limitation of this approach is that changes to the microbiota induced by diet are generally quite variable between patients and can depend on an individual's microbiota prior to intervention. And patient compliance is also a concern, particularly in the very strict diets. Now, regarding high fiber diets, several large cohorts of melanoma patients from the US, Australia, and the Netherlands demonstrated how a high fiber diet modulates the microbiome and results in a better response to immunotherapy, better progression-free survival. Additional studies that were presented at AACR in 2023 showed that high fiber dietary interventions, in which patients received a fiber-enriched diet for six weeks, was feasible and that the high fiber diet resulted in a rapid shift in the gut microbiota toward fiber-responsive short chain fatty acid-producing taxa and a shift of the metabolome, with increase in the short chain fatty acid acetate, Omega-3, Omega-6, polyunsaturated fatty acid, and tryptophan metabolites. Prebiotics can also promote the growth of beneficial microbial species in the gut by providing targeted nutrition. And one example of a prebiotic that was shown to enhance immunotherapy efficacy in mouse models is castalagin, which is isolated from the camu-camu berry. Castalagin directly binds the outer membrane of ruminococci and promotes their growth, which has been shown to increase the CD8-positive T-cell activity and anti-PD-1 efficacy. Now, since prebiotics rely on the presence of beneficial taxa already in the host microbiota, symbiotics, which refers to the administration of the appropriate prebiotic and probiotic together, may prove in the future to be more effective than using either separately. Dr. Diwakar Davar: Certainly, these dietary interventions can be very exciting and certainly we do know of several colleagues who are doing these diet interventions, though compliance with any kind of dietary intervention may be a challenge that decides how effective such an approach is going to be. So microbial therapies in general are still at a relatively early stage of development. And it'll be exciting to see how they advance. What approaches are you excited about? What is on your radar? Dr. Ben Boursi: There are many exciting works that are currently ongoing, and to emphasize just a few: there are many clinical trials in immunogenic tumors, in addition to melanoma, for example, renal cell carcinoma, and non-small cell lung cancer, that also evaluate different modulation protocols. We should remember that one size does not fit all, and different tumors have different microbiomes. We have a project in collaboration with MD Anderson in MSI-high patients with exciting initial results. Another study that was initiated at Sheba is using microbial modulation in order to improve TIL therapy (to overcome resistance to TIL and T-cell exhaustion). There are also studies that try to change the pharmaco-microbiome, for example, to eradicate bacteria that inactivates the chemotherapy agent, gemcitabine, in pancreatic cancer patients. And there are groups that try to identify recipients that will respond to microbial modulation and to generate better donor-recipient matching algorithms. There are already signatures like TOPOSCORE that was presented at ASCO 2023 that try to predict response to immunotherapies through the ratio between harmful and beneficial bacteria. Now, there's also more basic science work, for example, bacterial engineering. There was a wonderful study from the Fischbach group in Stanford that demonstrated how Staphylococcus epidermidis engineered to express melanoma tumor antigens was able to generate a systemic tumor-specific response in mice models when applied topically; functional imaging of the microbiome, for example, FDG uptake in the colon can reflect microbial diversity and response to immunotherapy; works that characterizes other microbiomes such as the urinary and skin microbiomes, and their interaction with the gut microbiome; and studies of the nonbacterial component of the microbiome, mainly phages and fungi. But for me, the most important word should probably be collaboration, because without joining forces internationally, we won't be able to understand the human metaorganism, the variations according to geography, ethnicity, lifestyle, diets, and much more in the microbiome. And this is crucial in order to really understand the complex tumor ecological niche within the human host. Dr. Diwakar Davar: I think one of the key points that you just mentioned is collaboration. That's going to be very, very critical as we move this forward for many reasons, including the unexpected impact of geography upon the composition of the gut microbiome in work that has been published by many groups, but also including ours in a paper that we published about a year ago now. So, Dr. Boursi, thank you for your great work in this area. Thank you for sharing your insights with us today on the ASCO Daily News Podcast. This is a very difficult time for all of you and your colleagues in Israel, and we thank you so much for taking such a great deal of time out of your busy workday to spend some time with us. Dr. Ben Boursi: Thank you very much. Dr. Diwakar Davar: Thank you to all our listeners today. This is a very exciting area. This is an area where we are discovering more every day than we knew just up until the day prior. You will find the links to the studies that were discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take the time to rate, review, and subscribe wherever you get your podcast. 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. Guests' 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 Dr. Ben Boursi 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. Ben Boursi: No relationships to disclose.
El Maestro Speaks with Freddie of @Fdg stages. Freddie is a vlogger/content creator who focuses on creating content that highlights Igorot cultures and tradition. He also owns the #badthewrong cafe in La Trinidad Benguet #igorotPodcast #kankanaeyPodcast #podcast #elmaestrspeaks #torogitalks #FDGSTAGES Don't forget to check the Sponsors of this Podcast by clicking the Link below.. This podcast is sponsored by the following. Check them out by clicking the link: 1. Millennial TECH. https://www.facebook.com/melltech/ 2. Cyspace Tech https://www.facebook.com/cyspacetech/ 3. MONAPHLORE's EGG POULTRY https://www.facebook.com/MonaPhloreEggPoultry/ 4. BMEP damdamag/local https://www.facebook.com/igorotlocalfilmmaker/ 5. Joemar P. Sacpa https://www.facebook.com/joemar.pasuli 6.Frederick Wallang https://www.facebook.com/frederick.wallang 7. CarlTech Repairs https://www.facebook.com/CarlNgalides. 8. Dem's Auto Performance +639503867369 --- Send in a voice message: https://podcasters.spotify.com/pod/show/el-maestro-speaks/message
On vous attend ce samedi 6 mai au Reset Bar à Paris (Châtelet) à partir de 17h ! Le lieu est réservé, il suffit de dire que vous venez pour la soirée FDG. A bientôt !
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.13.528352v1?rss=1 Authors: Inibhunu, H., Chameh, H. M., Skinner, F., Rich, S., Valiante, T. A. Abstract: Discerning the contribution of specific ionic currents to complex neuronal dynamics is a difficult, but important, task. This challenge is exacerbated in the human setting, although the widely-characterized uniqueness of the human brain as compared to preclinical models necessitates the direct study of human neurons. Neuronal spiking frequency preference is of particular interest given its role in rhythm generation and signal transmission in cortical circuits. Here, we combine the frequency-dependent gain (FDG), a measure of spiking frequency preference, and novel in silico analyses to dissect the contributions of individual ionic currents to key FDG features of human L5 neurons. We confirm that a contemporary model of such a neuron, primarily constrained to capture subthreshold activity driven by the hyperpolarization-activated cyclic nucleotide gated (h-) current, replicates key features of the in vitro FDG both with and without h-current activity. With the model confirmed as a viable approximation of the biophysical features of interest, we applied new analysis techniques to quantify the activity of each modeled ionic current in the moments prior to spiking, revealing unique dynamics of the h-current. These findings motivated patch-clamp recordings in analogous rodent neurons to characterize their FDG, which confirmed that a biophysically-detailed model of these neurons captures key inter-species differences in the FDG. These differences are correlated with distinct contributions of the h-current to neuronal activity. Together, this interdisciplinary and multi-species study provides new insights directly relating the dynamics of the h-current to neuronal spiking frequency preference in human L5 neurons. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.25.525587v1?rss=1 Authors: Peters-Founshtein, G., Gazit, L., Naveh, T., Domachevsky, L., Korczyn, A., Bernstine, H., Groshar, D., Marshall, G., Arzy, S. Abstract: Orientation is a fundamental cognitive faculty, allowing the behaving self to link his/her current state to their internal representations of the external world. Once exclusively linked to knowledge of the current place and present time, in recent years, the concept of orientation has evolved to include processing of social, temporal, and abstract relations. Concordantly with the growing focus on orientation, spatial disorientation has been increasingly recognized as a hallmark symptom of Alzheimers disease (AD). However, few studies have sought to explore disorientation along the AD continuum beyond the spatial domain. 51 participants along the AD continuum performed an orientation task in the spatial, temporal and social domains. Under functional magnetic resonance imaging (fMRI), participants determined which of two familiar places/events/people is geographically/chronologically/socially closer to them, respectively. A series of analyses revealed disorientation along the AD-continuum to follow a three-way association between (1) orientation domain, (2) brain region, and (3) disease stage. Specifically, participants with MCI exhibited impaired spatio-temporal orientation and reduced task-evoked activity in temporoparietal regions, while participants with AD dementia exhibited impaired social orientation and reduced task-evoked activity in frontoparietal regions. Furthermore, these patterns of hypoactivation coincided with Default Mode Network (DMN) sub-networks, with spatio-temporal orientation activation overlapping DMN-C and social orientation with DMN-A. Finally, these patterns of disorientation-associated hypoactivations coincided with patterns of fluorodeoxyglucose (FDG) hypometabolism and cortical atrophy characteristic to AD-dementia. Taken together, our results suggest that AD may constitute a disorder of orientation, characterized by a biphasic process as (1) early spatio-temporal and (2) late social disorientation, concurrently manifesting in task-evoked and neurodegenerative changes in temporoparietal and parieto-frontal brain networks, respectively. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Exserv, Hugo et Maxime vous présentent le programme de FDG pour 2023 ! Au menu : un revirement pour la chaîne Twitch, un nouveau palier à atteindre pour la saison 6, l'annonce de la Blackliste III et une surprise pour fêter les 100 épisodes en Mai. On vous explique tout ça rapidement, merci de nous soutenir sur Patreon pour faire vivre l'émission jusqu'à l'épisode 200 ! Le lien du formulaire pour la 100ème : https://docs.google.com/forms/d/e/1FAIpQLSccVTB--mWbMUlV1E_9lbXy0oNOhcW2uanoYZ8mdf3WcnezlA/viewform Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkN
Diffuse Large B-Cell Lymphoma or DLBCL is the most common type of lymphoma. Much progress has been made in treatment of the disease lately, particularly with emergence of CAR T-cell therapy, but not all patients are benefiting from it. This episode of Cancer Topics features Drs. Loretta Nastoupil and Chijioke Nze exploring treatment approaches for two cases of refractory DLBCL: a 60-year-old man with no comorbidities (1:30) and a 39-year-old woman with HIV (18:35). The guests also discuss improving patient access to CAR T-cell therapy and managing its toxicities (10:35), as well as emerging therapies for DLBCL (14:30). To learn more about management of refractory DLBCL, check out the ASCO course linked bellow. Guest Disclosures:Loretta Nastoupil, MD: Honoraria – Gilead Sciences, Novartis, Bayer, Janssen Oncology, TG Therapeutics, Bristol-Myers Squibb, ADC Therapeuitcs, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche; Research Funding – Janssen Biotech, Celgene, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Chijioke Nze, MD, MPH: No Relationships to Disclose Resources: ASCO Course: Second-line Therapy for Relapsed/Refractory Diffuse Large B-cell Lymphoma (Free to Full and Allied ASCO Members) ASCO Podcast: Cancer Topics - New Therapies for Lymphoma (Part 1) ASCO Guideline: Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor (CAR) T-Cell Therapy ASCO Article: Navigating the Evolving Treatment Landscape of Diffuse Large B-Cell Lymphoma If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Loretta Nastoupil: So, I do have optimism that as we have more and more treatment options entering into the treatment landscape, we'll have fewer patients that are experiencing a refractory disease, and potentially succumbing to the lymphoma. Hello, my name is Dr. Loretta Nastoupil, I'm an Associate Professor and Deputy Chair of the Department of Lymphoma and Myeloma, at the University of Texas MD Anderson Cancer Center. Welcome to this ASCO Education podcast episode. It's my pleasure to welcome Dr. Chijioke Nze. Dr. Chijioke Nze: Hello, everyone. I'm Dr. Chijioke Nze, a Hematology/Oncology fellow at MD Anderson, I'll be co-hosting this episode with Dr. Nastoupil. Dr. Loretta Nastoupil: We've seen notable advances in diffuse large B-cell lymphoma research lately, with novel treatments including CAR T-cell therapy, offering the prospect of long-term remission for some patients, yet many patients are not even receiving second-line or later therapy, and even fewer are treated beyond the second line. How do you approach a patient with refractory diffuse large B-cell lymphoma? In today's episode, we'll explore strategies for management of refractory diffuse large B-cell lymphoma through two patient cases. So, Dr. Nze, walk us through our first case. Dr. Chijioke Nze: Our first case is Frank. Frank is 60 years old and has no comorbidities. He presented with severe back pain in September 2021, and was evaluated locally. He had a CT scan that showed retroperitoneal mass, prompting further evaluation. He had a biopsy of the left retroperitoneal mass in November 2021, which was consistent with diffuse large B-cell, germinal center B-cell of phenotype Ki-67 of 90%. He had a subsequent PET-CT scan, which showed a large conglomerate, and invasive left retroperitoneal hypermetabolic mass with satellite nodularity and contiguous bulky retroperitoneal adenopathy. He had bulky, FDG-avid metastatic retrocrural and intrathoracic adenopathy as well. He was treated with R-CHOP for six cycles, and at the end, achieved complete remission. He had a PET-CT a year later that showed new and worsening intensely FDG-avid abdominal adenopathy. This was new from a PET scan he'd had in January 2022 of the same year. He had a biopsy of this retroperitoneal adenopathy, which was consistent with relapsed diffuse large B-cell germinal center phenotype, also Ki-67 of 90%. Locally, he was treated with ICE, times five cycles, and had a follow-up CT scan at the end, which showed persistent bulky nodal disease with periaortic regional nodes with double 5, consistent with persistent disease. He also was found to have new and more conspicuous nodes in other areas as well. He presented for his first visit at MD Anderson in September 2022. Dr. Nastoupil, when you see a patient like this coming into your clinic, what's your typical approach? Dr. Loretta Nastoupil: For a diffuse large B-cell lymphoma, we are always hoping for cure with frontline rituximab, containing anthracycline-based chemotherapy. And so, it's always a gross disappointment when patients experience relapse. The timing of that relapse right now informs our current approach. And the reason I mention that, is because there have been three large randomized studies conducted and reported out just in the last year demonstrating that CAR T-cell therapy is the preferred option for patients who experience either primary refractory disease, or relapse within 12 months. And that is because they resulted in better outcomes than standard salvage-based chemotherapy and high-dose therapy autotransplant in the setting of chemosensitive disease. I have to acknowledge, of the three studies that were done, two were positive trials, so that's why currently, we have axi-cel or Axicabtagene ciloleucel, or Lisocabtagene maraleucel, and not tisa-cel or Tisagenlecleucel, as CAR T-cell therapy options. And again, that's because two of the three studies were positive trials. Now, the challenge is why would we have two positive studies in one negative trial? There are a lot of caveats to how those studies were conducted, but I think one of the biggest important lessons to be gained is that if you're going to consider CAR T for these high-risk patients, you want to do it as soon as possible, because that delay from identifying CAR T as a preferred option to actually infusing cells in a disease-- in a case particularly like this, where patients may have bulky, aggressively-behaving disease - that prolonged time may actually have an impact on outcomes. Dr. Chijioke Nze: Excellent. Thank you. So, you've mentioned he had an early relapse. How would you define early relapse in this patient population? Dr. Loretta Nastoupil: Thinking back to how we've been approaching diffuse large B-cell lymphoma over the last two decades, the PARMA study, which was done prior to Rituximab, suggested that for patients who had chemosensitive disease to a platinum-based salvage chemotherapy, which generally, was at least a partial response on CT, if they went on to high-dose therapy autologous stem cell transplant, 50-60% of those patients could anticipate cure. Whereas for the folks who continued on salvage chemotherapy, 10-20% of those patients had favorable outcome. So, we generally do try salvage-based chemotherapy, and for patients with chemosensitive disease, go on to high-dose therapy autotransplant. However, in the modern era where we've approached patients who've had rituximab as part of their frontline therapy, at least two studies - the ORCHARD study, and the CORAL study suggested that only 20% of patients who relapse in the post-rituximab era, particularly within 12 months, were successfully salvaged with platinum-based chemotherapy and high-dose therapy autologous stem cell transplant. Now, fortunately for patients who fail salvage, we have had CAR T-cell therapy as an option based off of three pivotal phase II studies, demonstrating about 40% of patients could anticipate a cure with CAR T-cell therapy. So, it only made sense to try and move that therapy up into second line, and the preferred population was those that had progressed within 12 months of frontline rituximab and anthracycline-based chemo. Now, to qualify for those studies, patients had to be considered fit for the control arm, which was salvage and auto transplant. Nonetheless, I do think for a patient like this, who's 60, without any other significant comorbidities, whose biggest challenge to longevity of life is his aggressive lymphoma, CAR T-cell therapy should be considered as soon as possible for this patient. Dr. Chijioke Nze: Is there still a role for high-dose therapy and autologous transplant in the new era, given the efficacy shown with CAR T-cell therapy? Dr. Loretta Nastoupil: I think there is. And the reason why I say that is, the trials that were done really did focus on the highest-risk patients, which were those with primary refractory disease or those who progress within 12 months of frontline. Now, there are patients that will have later relapse. And so, I do think for those patients, particularly those who are young and otherwise fit, should be approached first with a platinum-based salvage chemotherapy, in the setting of chemosensitive disease, proceed onto high-dose therapy and autologous stem cell transplant. Now, what do we do for those patients who have a late relapse but are otherwise older, or who have comorbidities that would make them suboptimal candidates for the high-dose therapy preceding stem cell transplant? I have a couple other options for those patients - so, there was a trial done with liso-cel for patients who were otherwise older, or not fit for intensive therapy. It's a single-arm phase II without a randomized comparison, but also demonstrated that liso-cel in second-line, later relapsed patients who are not fit for intensive therapy, resulted in comparable outcomes to what we would anticipate on that third-line or later setting. We also have other non-CAR T-cell therapy options, such as tafasitamab, which is a naked CD19 antibody, which has been combined with lenalidomide in the L-MIND study, again, for patients without primary refractory disease and who would not be appropriate candidates for intensive therapy. So, I do think we have alternative options, it's just when we look at the totality of the data right now, my conclusion is that CAR T-cell therapy, particularly for high-risk patients, is the most likely chance to result in cure. Dr. Chijioke Nze: Excellent. In a patient who we are considering CAR T-cell therapy, what are some of the short-term and long-term consequences, or toxicities that we should worry about? Dr. Loretta Nastoupil: One of the challenges right now with CAR T, and why it's still only available in specialized centers, is the acute toxicity, which is really a derivative of its mechanism of action. We take patients' own T-cells, we use a viral vector to introduce extracellular receptor, but also a co-stimulatory molecule. So, once these cells engage their antigen, sort of prime to react to that, and that can lead to pretty rapid T-cell expansion, release of cytokines, recruitment of other inflammatory cells to that tumor bed, and as a result, a large portion of patients can anticipate to experience cytokine release syndrome, which again, is the result of the activation of these T-cells, the expansion and the recruitment of other inflammatory cells. Fortunately, for most patients, this results in fever alone that can be managed with supportive measures. Occasionally, they'll have concomitant hypoxia or hypotension, and unfortunately, few patients will have significant or severe toxicity. The other toxicity that's less easily manageable or less predictable is the neurotoxicity that can vary according to patient-specific characteristics, such as age, and the amount of tumor burden, their performance status going into CAR, but even more importantly, the construct that's utilized, with highest rates of neurotoxicity associated with axi-cel. Again, likely speaking to its construct and the CD28 costimulatory domain that is unique to axi-cel. As a result of these acute toxicities, patients are required to stay within two hours of their treating center for the first four weeks, and they're also discouraged from operating heavy machinery, such as driving, for the first eight weeks following CAR T. So, I do you think this creates some barriers to access to this therapy, particularly the patients that are treated in community settings that may reside long distances from these certified CAR centers. Dr. Chijioke Nze: So, you mentioned that obviously, given the specialized care needed for the CAR T therapy, that they're kind of localized in certain sites. What are some of these issues with access that you're noticing both in the logistics of giving CAR T, and also in patient access? Dr. Loretta Nastoupil: I'm hoping we're going to address one of those issues right now, which is, education and awareness, because we've had these three randomized studies, and two being positive readouts just in the last year. It's important to get the message out that CAR T-cell therapy for high-risk early relapsed refractory large cell lymphoma patients can result in a significant improvement in event-free survival and progression-free survival over the standard of care. And so, being aware that this therapy can result in more favorable outcomes is step one. Step two is, we have to ensure that there are minimal barriers to getting those patients into these treating centers as quickly as possible. So, recognizing who delivers the care - is it your traditional stem cell transplant physician? Is it a lymphoma doctor? What centers are certified? Some of these issues can be addressed with quick internet searches. So, for instance, in our center, we have a 1-800 number for anyone who's interested in CAR T-cell therapy that connects them directly to a CAR T coordinator who can help them understand do they meet the FDA-approved indication? Would they be interested in seeking consult? And we try and prioritize getting those patients in the door as soon as possible since time likely does have an impact on outcomes. And then, partnering with our community oncologist - you're going to be the primary oncologist for these patients leading up to CAR, and then after that four-week window, when we're keeping the patients in close proximity to our centers, we often send them back. And so, making sure that they're comfortable knowing what potential late toxicities to be on the lookout for, which include B-cell aplasia and risk for infection, or prolonged cytopenias, beyond just lymphopenia. And so again, there's a need for education and partnering with our community sites to make sure that there is successful handoff of these patients back after they've completed the monitoring for the acute toxicity. And then, really trying to explore opportunities to utilize some of the better tolerated CAR T, such as liso-cel, in your non-traditional academic centers. Those that are equipped to handle phase I studies or stem cell transplant, for instance, may not be affiliated with the university. So, I think those are all types of strategies that could be employed to try and improve access for patients. Dr. Chijioke Nze: And then, you mentioned the liso-cel, but in some of the toxicities, are there ways of predicting which patients will do better or worse? Are there ways to reduce toxicities? And is there any hope for things such as outpatient administration of CAR T? Dr. Loretta Nastoupil: So, my answer today may improve over time as we get larger numbers and more experience, but what we currently understand is that the patient performance status, their degree of tumor, how quickly that tumor is increasing, LDH and some inflammatory markers such as CRP or ferritin pretreatment can provide some insight into a higher risk of toxicity. And then obviously, the construct that's utilized. Again, axi-cel has higher rates of neurotoxicity. All will have some form of cytokine release syndrome, generally speaking, but rates of grade three or higher are quite infrequent, particularly with liso-cel and tisa-cel. So, it's multifactorial. That then raises the question, can we do anything to alter those modifiable risk factors? Can we reduce the disease burden? Can we improve the performance status? Can we do anything to reduce the inflammatory markers pre-treatment? And so, those are strategies that are being discussed, and I think in general, as we get more effective therapies that enter into the treatment landscape, it's probably some of the best ways to try and reduce some of those risk factors. Dr. Chijioke Nze: Rounding that up, are there any exciting developments or things to look out for, for exciting therapies in the relapse setting? Dr. Loretta Nastoupil: A couple of things beyond CAR T that I think we should all be aware of and anticipate to be in our toolkit relatively soon; probably, one of the most exciting, is the development of the bispecific antibodies. So, another challenge with CAR T is the requirement to collect these patients' own T-cells and send them off to a central manufacturing site, and the turnaround time can be anywhere from 3-4 weeks. And again, in a situation where you have an aggressive disease, that can be a long time to wait. And so, is there any treatments that are more readily available, that again, will be effective at reducing disease burden? And so, by specifics kind of fit those unmet needs to some extent - you have essentially two heads; one head is going to bind the endogenous T-cells that eliminates the need to leukapherese these patients and manufacture, and then the other head is going to generally engage CD20, which we know is an effective targeted antigen, particularly in B-cell lymphomas. And there are a number that are under development. We saw preliminary phase II data with glofitamab, epcoritamab, as well as combination strategies with mosunetuzumab. So, I do have optimism that the bispecific antibodies will potentially enter into the treatment landscape. I anticipate they'll probably be used first post-CAR T, but will likely move their way into earlier lines of therapy. I've already mentioned tafasitamab in combination with lenalidomide, which is an effective non-chemotherapy option. We have antibody-drug conjugates, such as Loncastuximab, which is a CD19 antibody-drug conjugate. It's essentially targeted delivery of chemotherapy, and it looks to have a pretty promising activity as a single agent in that third-line or later space, and then polatuzumab, which is a CD79b antibody drug conjugate, in the relapse setting has been combined with bendamustine and rituximab, but also demonstrated significant improvement in the frontline setting in the POLARIS study where vincristine was replaced with polatuzumab. So, I do have optimism that as we have more and more treatment options entering into the treatment landscape, we'll have fewer patients that are experiencing refractory disease, and potentially succumbing to the lymphoma. Dr. Chijioke Nze: And then, one additional question: How do you approach a patient who is not quite as fit, in thinking about what their options are for later-line therapies? You already mentioned some of these, but which of those would you prioritize in this setting? Dr. Loretta Nastoupil: Again, as we get more experience, we develop skills that help us sort of navigate all these different options. In my practice, if I'm even considering CAR T, I'm going to delay bendamustine until after I've collected those cells. I think that's one caveat that-- we do get nervous about the quality of those autologous CAR Ts if they're generated in someone who's had recent exposure to bendamustine. So, that may help me sequence that later on. We have questions right now about what's the optimal sequencing of CD19-directed therapy because we have several options beyond just CAR T-- As I mentioned, we have Lonca, we've got tafasitamab and lenalidomide. Currently, we don't have prospective data that really informs that question, and there's a number of research studies underway to try and help us understand if there is a preferred sequence, or even if it matters how we handle CD19 targeting. For my older, frailer patients where I'm really worried, they're not going to be able to tolerate something like liso-cel, or they're not going to be able to have that caregiver, and they're uncomfortable relocating to an area where CAR T might be available, my general approach right now is to consider tafasitamab and lenalidomide first in that relapse setting, followed by either Lonca or Pola-BR. Selinexor is another option. It's an oral agent, though again, in my opinion, if we look at the totality of the data, may be less effective than the other options. So, I might reserve that as a last option for someone, again, with relapsed/refractory large cell. Dr. Chijioke Nze: Excellent. Thank you. This has been very helpful. Dr. Loretta Nastoupil: All right. So, Dr. Nze, now I'm going to turn the table and ask you some questions. I'm going to change this up a little bit - she's now a 39-year-old female. She has significant comorbidities. She has HIV, and again, large cell lymphoma. So, let me walk you through her case, and then we'll discuss some of the challenges, again, in a very different scenario, albeit a similar disease. So, our female is, I mentioned 39, pre-existing HIV, she's treated frontline with six cycles of R-CHOP and intrathecal methotrexate for CNS prophylaxis. Because of her comorbidities, again, not well controlled HIV, she also has a poor functional status at the time of relapse. This was a couple years ago, and CAR T was not an option in second line, though she is someone who had a relapse that was beyond 12 months. So, for her second-line approach, because of her comorbidities, she actually receives rituximab in combination with high-dose cytarabine, dexamethasone, and oxaliplatin for three cycles, and actually achieves a chemosensitive disease and is referred to our stem cell transplant colleagues. Unfortunately, at that time, due to comorbidities, she was deemed not to be an appropriate candidate for high-dose therapy, and she's been monitored for signs of relapse. Despite being in the minority, she actually does not have a recurrence of her lymphoma but has a number of other, again, challenges in regards to her comorbidity, including multiple infections, resulting in recurrent hospitalizations. And so, it's always been a challenge for me in being intimately involved in her case, deciding when she's presenting, how alarmed to be about recurrent lymphoma versus infection, and how I might approach her in the setting of relapsed large cell lymphoma. So, what role does prior type and response to therapy play in treatment selection at your next line of treatment? Dr. Chijioke Nze: I think in this patient, it sounds like she got one adequate therapy on and the initial presentation with R-CHOP, and then with IT chemotherapy as well. She looked like she had a good response. I think the fact that she achieved a complete response and the duration of her response, lets me know that she likely has chemosensitive disease. This, in turn, helps me to pick what to do next. As you mentioned previously, we know how efficacious the CAR T therapy is, but in someone like her who had a long duration, trying salvage therapy and proceeding to autologous transplant might make sense. I'd be interested in your thoughts. Dr. Loretta Nastoupil: Yeah, I agree. And I think part of the challenge, particularly when we're facing patients with HIV, they're often excluded from prospective studies. And so, we're often in a scenario where we may not have the wealth of data to inform our treatment decision. But I do think in general, comorbidities play a major role-- we're navigating treatment options. Because again, traditionally, we've used intensive chemotherapy as our mainstay of treatment, and there are clear criteria that patients generally should meet that help us predict how likely they are to have significant or severe toxicity from high-dose therapy. And this is a prime example of even though she was young, her comorbidity made her a poor candidate for intensive therapy. I think the other sort of non-clinical factors that we sometimes take into consideration, because CAR T was approved off of single-arm phase II studies, again, none of which would've included someone like her, because of her HIV status, how do we extrapolate-- for instance, if she had relapsed in that third-line space, and suggesting that she did not have significant infection or other significant comorbidities, do we have experience to proceed with an autologous CAR in that setting? So, again, there've been a few cases where we have case reports where people have reported on their standard of care outcomes, particularly with CAR T in patients with active HIV disease, but one of the concerns I have in these scenarios is very selected. If you have active infection, that can make the acute toxicity with CAR significantly worse. And so again, we're trying to navigate a sort of limited data zone to try and help her and choose the right therapy. Again, you've met this patient with me, you helped care for her for some time, and you have a unique experience of also practicing in a county hospital where comorbidities, particularly, like HIV, can be much more common. What is your perception regarding barriers to accessing CAR T as it pertains to social factors, clinical factors, and again, this is a case that highlights some of those issues. Dr. Chijioke Nze: You mentioned at first that she had uncontrolled HIV. So, I think which, one, speaks to her treatment reference of her non-malignancy-related diseases, and trying to get that under control would be one of the first things I could think about. Thinking about how her care is managed and what kind of support she has are very important for us to think about as well. The other thing that's very important is, a lot of patients who we're seeing in the community may not have access to such specialized centers such as MD Anderson, where patients do have access to clinical trials and CAR T therapy. So, patients who are unlike her, who might qualify, may not actually be able to get these therapies as well. Part of the reason is, it can be insurance status, which is what we see in a lot of our patients. So, a barrier to get into the door. And then too barriers, lack of social support can be a big issue as well. And then there's also a big push in the community to improve the trust and awareness of these novel therapies, as you've mentioned. So, in a lot of the community practice, some of the community practitioners may not be comfortable with these, and a lot of the patients may not have heard of these new technologies, and also want to defer trying new therapies before having other people try new therapies before they consider them themselves. I think all these things present specific significant barriers to patients in the community. One, their ability to adhere to care, two, their insurance and their ability to get care and the financial toxicities associated with that. And then third, really understanding the options that are available. Dr. Loretta Nastoupil: And again, just to try and illustrate a couple other points. You know, we use a case here, which is a real case, with significant comorbidities such as HIV, which again, is something that is not frequently encountered, and will have a large impact on treatment selection. What if I just told you this patient has comorbidities, but she has moderate type-2 diabetes, and as a result, she has mild renal insufficiency, ejection fraction is actually adequate, would you have done anything different in this case? Dr. Chijioke Nze: No. I think in this particular case, I do think the fact that she did have a good response for a long duration of time, and did seem to have chemosensitive disease, I would probably still have tried a salvage therapy and autologous transplant in this patient. In the event that she was refractory, or had early relapse, and in that case, I would consider her to not be chemosensitive and would definitely have sought some more active therapies such as CAR T cell therapy through available products. Dr. Loretta Nastoupil: And then one last question for you: What if we just changed her age and we made her 79, but no other significant comorbidities, how would that have impacted your approach? Dr. Chijioke Nze: I'm going to turn that one over to you, I'm not exactly sure how I would treat with older patient with the same disease. Dr. Loretta Nastoupil: That's fair. So, if you have an older patient who has a late relapse, but not necessarily someone you would consider appropriate for salvage chemotherapy and high-dose therapy, then I think tafasitamab and lenalidomide would be probably my first choice in that setting, just based off of the L-MIND study. Dr. Chijioke Nze: Thank you, Dr. Nastoupil, for a great discussion of the management of diffuse large B-cell lymphoma. And thank you to all our listeners. We appreciate you tuning in to this episode of the ASCO Educational podcast. 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.
Welcome back! Happy New Year! Strickland in as short notice opponent in what we feel is one of the top plays on the card. We are proud to announce our partnership with Betstamp and our looking forward to brining you sharper angles and cleaner plays. We had a chance to chop it up with Damon Jackson. He is hunting a finish. FDG sounds good. Twitter: @mcgmma. @mma_breakdowns IG. - Twitter. - Youtube: @Donttappodcast https://withkoji.com/@DonttapCulture https://youtube.com/channel/UC04L_oMTKKnCZplmTg_NyrQ https://open.spotify.com/show/5CWNwtOVSMnB2dzTBxFdPg?si=Ur-xpwSiTtmMI88CctgRvQ&utm_source=copy-link
Dans une industrie où les suites sont plus un réflexe qu'une tendance, rares sont les jeux à pouvoir traiter l'idée qu'ils soient les derniers de leur licence. C'est pourtant le cas de cet Uncharted 4, qui nous présente un Nathan Drake qui n'arrive pas à raccrocher alors qu'il est clairement en bout de course. Et si l'équipe de Neil Druckmann et Bruce Straley arrive à sortir ses meilleurs séquences sur cette opus (coucou Madagascar), elle pose aussi un regard lucide sur une formule qui a fait son temps au sein du AAA moderne. FDG revient sur cet opus presque meta, oh yes yes yes yes yes. Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : https://discord.gg/YTGbSkNLa chaîne Twitch : https://www.twitch.tv/findugamejv
Lung Cancer Histology and Staging*Workup for a nodule that is concerning: **Ensure there is a dedicated CT scan of the chest to evaluate **Try to obtain old imaging; the rate of change is important **Can get PET, but even if a lesion if not FDG-avid, but growing quickly we should consider biopsy anyway**Referral to pulmonary medicine, who can assist with biopsy and also regional lymph node evaluation (important – more below)**PFTs are often ordered because it provides information about lung function in anticipation of possible surgery for treatment Lung Cancer Histology: *Non-small cell lung cancer (NSCLC)**Umbrella term for a variety of cancers**Increased risk in smokers**More common types: ***Adenocarcinoma (~50% of all lung cancers)****Most common overall; cancer of the mucus producing cells****IHC: TTF-1, NapsinA, CK7 positive***Squamous Cell Carcinoma (22.7%)****More often seen in patients with a smoking history ****IHC: p63 positive and cytokeratin pearls***Remaining ~15% are the other types of lung cancer / mixed histologies**Small cell lung cancer (SCLC)***Neuroendocrine tumor with very different pathology***Much more aggressive than NSCLC***Oncologic emergency***IHC: Chromogranin and synaptophysin positive IHC pearls: TTF-1 usually means lung cancer (but can be negative in squamous cell lung cancer). This will be important in the future (we promise :])*Staging for NSCLC:**Nodal evaluation: lymph node evaluation is part of the workup for NSCLC**Single digit = central/mediastinal nodes (higher risk)**Double digit = peripheral/hilar/intrapulmonary lymph nodes (lower risk)**“R” vs. “L” is direction *Pearl: Why is this important? If there is nodal involvement, systemic therapy is going to be necessary *Putting it all together: **T: Tumor size: T1-4**N: Nodal involvement***N0: no nodal involvement ***N1: Nodes closest to the primary tumor (double digits)****Ipsilateral peribronchial, hilar, intrapulmonary ***N2: Further away (single digit)****Ipsilateral mediastinal and/or subcarinal LN***N3: Contralateral any node or supraclavicular LN **M: Metastasis – in lung cancer, patients with certain patterns of metastatic disease are still curable! ***M0: no mets***M1a: Contralateral lobe, pleural effusion or pericardial effusion à these are generally still curable!***M1b: single site of metastatic disease à these are generally still curable!***M1c: multiple sites of metastatic disease à these are generally not curable*Staging for SCLC: **Limited stage - meaning it can fit in “one radiation field”**Extensive stage - does not fit in “one radiation field”*Once lung cancer is diagnosed:**Go to NCCN to learn the flow of ongoing management**Complete staging (if not already done):***CT C/A/P (don't necessarily need if a PET scan is done)***PET Scan***MRI brain à in general this is needed, but there are some exception to this (see NCCN)**Referral to pulmonary for nodal evaluationReferences: NCCN.orghttps://doi-org.proxy.library.vanderbilt.edu/10.1016/j.semcancer.2017.11.019-Article about IHC markers for lung cancer Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast
En guise de conclusion de cette saison 4, l'équipe de FDG monte à bord du Normandy pour revenir sur le premier opus de Mass Effect, la trilogie culte de Bioware. Après le succès de KOTOR, le studio Canadien veut développer son propre univers et au passage, sortir un RPG grand public sur console HD. Dans la peau du commandant Shepard, on explore des planètes hostiles, on drague des aliens sexy et on sauve la galaxie à coups de fusil à pompe ou de bons mots. C'est ça la SPECTRE Life. Mais malgré quelques bonnes idées sur sa gestion des dialogues, Mass Effect peine à convaincre sur les autres aspects de sa proposition ludique. Et si les épisodes suivants sauront faire quelques choix judicieux pour améliorer la formule, jamais elle n'atteindra les sommets qu'on pouvait projeter en elle. Reste plus qu'à moissonner. Et réessayer ?Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameLe lien de la chaîne Twitch : https://www.twitch.tv/findugamejvLe lien du Twitter : https://twitter.com/findugamejvRejoignez le club de lecture sur Discord : discord.gg/YTGbSkN
Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we sit down with guest pulmonologist Dr. Greta Dahlberg to discuss how she thinks about and works up lung nodules concerning for malignancy.Lung nodules: * For discussions about incidental lung nodules and lung cancer screening, check out Episode 197 from our friends, The Curbsiders (link: https://thecurbsiders.com/podcast/197) * Nodule vs. mass:** “Micronodule” is
Début 2019, le marché du Battle Royale semble déjà saturé. Après le succès explosif de PUBG, Fortnite règne en maitre et les nouveaux prétendants sont mis K.O. à peine après avoir débarqué dans l'arène. Mais chez Respawn, on a justement pris son temps avant de faire le grand saut. En plus des bases solides de Titanfall, les équipes de Vince Zampella ont tout fait pour rendre Apex Legends unique, en misant sur le jeu en équipe et des hér... légendes aux capacités variées. Résultat : après sa sortie surprise, le titre trouve immédiatement son public et s'impose comme une référence, notamment grâce au soin apporté à son UX et son fameux "Ping system". Alors qu'il entame sa 13ème saison, FDG revient sur le dernier produit star du portefeuille d'Electronic Arts.Merci à nos patreotes qui financent l'émission sur https://www.patreon.com/findugameRejoignez le club de lecture sur Discord : discord.gg/YTGbSkNMerci à notre sponsor pour cet épisode, le Game Pass : https://www.xbox.com/fr-FR/xbox-game-pass
✋ Intervista con Fabio Millevoi, Direttore ANCE FVG e Futurista
Featuring an interview with Dr Ajai Chari including the following topics: Case: A man in his early 80s with newly diagnosed multiple myeloma (MM) presenting with new anemia and an IgA monoclonal spike (0:00) Case: A woman in her early 60s with newly diagnosed MM presenting with hypercalcemia and FDG avid lytic lesions (8:02) Updates from ASH 2021 on CAR (chimeric antigen receptor) T-cell therapy for MM (29:27) Data on bispecific antibodies at ASH 2021 (36:28) CME information and select publications
This week's View highlights the use of ICD therapy in ischemic vs. non-ischemic cardiomyopathy; what are the (FDG)-positron emission tomography (PET) and MRI findings, and abnormalities in patients with COVID-19; and a meta-analysis examining oral anticoagulation in AFib.
Image of the Year Ganna Blazhenets PET scans show long covid We discuss the SNMMI image of the year for 2021 Where FDG scans showed acute changes on the brain following COVID and for some subjects these changes were not gone at 6 months. https://jnm.snmjournals.org/content/early/2021/03/31/jnumed.121.262128 https://www.nuccast.com #Nuccast.com #UniversityofMelbourne #SNMMI #NIF #COVID #PET #NuclearMedicine #Podcast #MolecularMedicine #covid #longcovid Nuccast.com ,UniversityofMelbourne ,SNMMI ,NIF ,PET ,NuclearMedicine ,Podcast ,MolecularMedicine, Covid, Lobgcovid, FDG Please let me know what you think about the video versions of the podcast.I am also looking for new material so please get in touch with me if you can contributewith an interview.Direct link to iTuneshttps://itunes.apple.com/au/podcast/the-nuclear-medicine-and-molecular-medicinie-podcast/id1444565219?mt=2Older podcastshttps://podcasts.apple.com/au/podcast/the-nuclear-medicine-and-molecular-medicine-podcast/id94286547You can get the podcast page at both http://nuccast.com and http://www.nuccast.com with the feed to put into iTunes or juice or your favourite podcast software can be found at http://molcast.com/.The cardiac subset of the podcast can be found at http://cardiac.nuccast.com/Please pass on information about this podcast to your colleagues and to your CPD provider.Link to Video Link to Video fileLink to Audio file Link to Audio fileOr you can subscribe by entering your email address below and you will be informed of new episodesEnter your email address:Delivered by FeedBurnerMost importantly of all please help this podcast by contributing your opinions, Sound files, and emailsnucmedpodcast@gmail.comAll contributions welcome, especially as sound files to nucmedpodcast@gmail.com.
SNMMI 2021 Image of the Year Ganna Blazhenets PET scans show long covid We discuss the SNMMI image of the year for 2021 Where FDG scans showed acute changes on the brain following COVID and for some subjects these changes were not gone at 6 months. https://jnm.snmjournals.org/content/early/2021/03/31/jnumed.121.262128 https://www.nuccast.com #Nuccast.com #UniversityofMelbourne #SNMMI #NIF #COVID #PET #NuclearMedicine #Podcast #MolecularMedicine #covid #longcovid Nuccast.com ,UniversityofMelbourne ,SNMMI ,NIF ,PET ,NuclearMedicine ,Podcast ,MolecularMedicine, Covid, Lobgcovid, FDG Please let me know what you think about the video versions of the podcast.I am also looking for new material so please get in touch with me if you can contributewith an interview.Direct link to iTuneshttps://itunes.apple.com/au/podcast/the-nuclear-medicine-and-molecular-medicinie-podcast/id1444565219?mt=2Older podcastshttps://podcasts.apple.com/au/podcast/the-nuclear-medicine-and-molecular-medicine-podcast/id94286547You can get the podcast page at both http://nuccast.com and http://www.nuccast.com with the feed to put into iTunes or juice or your favourite podcast software can be found at http://molcast.com/.The cardiac subset of the podcast can be found at http://cardiac.nuccast.com/Please pass on information about this podcast to your colleagues and to your CPD provider.Link to Video Link to Video fileLink to Audio file Link to Audio fileOr you can subscribe by entering your email address below and you will be informed of new episodesEnter your email address:Delivered by FeedBurnerMost importantly of all please help this podcast by contributing your opinions, Sound files, and emailsnucmedpodcast@gmail.comAll contributions welcome, especially as sound files to nucmedpodcast@gmail.com.
In this episode, Jamie E. Chaft, MD, provides her expert perspective on new data from WCLC 2020 in early-stage NSCLC, with topics including:Updated results from ADAURA on HRQoL and DFS outcomes with or without postoperative chemotherapy after adjuvant osimertinibAn analysis of the ongoing ITACA study of personalizing chemotherapy based on biomarkers of drug resistanceFDG PET/CT adaptive radiotherapy in RTOG 1106The TALENT study in Taiwan screening nonsmokers for lung cancerPresenter:Jamie E. Chaft, MDAssociate Attending PhysicianThoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew York, New YorkContent supported by educational grants from Amgen; Bristol-Myers Squibb; Ipsen Biopharmaceuticals; Janssen Pharmaceutica NV; Jazz Pharmaceuticals; Regeneron Pharmaceuticals, Inc. & Sanofi Genzyme; and Takeda Oncology.Link to full program, including a downloadable highlights slideset, and ClinicalThought commentaries:http://bit.ly/2NzE6X6
There's so much going on in the ETF world right now as all kinds of trends, strategies, themes and companies collide in this hotter-than-ever market which is on pace to post another record year for inflows - and volume - in 2020. Next year could be even bigger too as many ‘Big Active' mutual fund firms representing $10 trillion in assets look to make up for lost time. So what should you watch for in 2021? Rather than do another “outlook” Bloomberg Intelligence's ETF team has come out with a report that highlights 21 ETFs to watch 2021. Analysts Athanasios Psarafagis, James Seyffart and Morgan Barna join us to go over their contributions to the full list, which are as follows: DFAU, SPGP, ICVT, VXUS, GBTC, SNPE, OVL, SQQQ, ARKK, SVAL, MSOS, VTI, QQQJ, KMED, BATT, NETL, IBUY, SPAK, USMV, FDG and LQD.See omnystudio.com/listener for privacy information.
There’s so much going on in the ETF world right now as all kinds of trends, strategies, themes and companies collide in this hotter-than-ever market which is on pace to post another record year for inflows - and volume - in 2020. Next year could be even bigger too as many ‘Big Active’ mutual fund firms representing $10 trillion in assets look to make up for lost time. So what should you watch for in 2021? Rather than do another “outlook” Bloomberg Intelligence’s ETF team has come out with a report that highlights 21 ETFs to watch 2021. Analysts Athanasios Psarafagis, James Seyffart and Morgan Barna join us to go over their contributions to the full list, which are as follows: DFAU, SPGP, ICVT, VXUS, GBTC, SNPE, OVL, SQQQ, ARKK, SVAL, MSOS, VTI, QQQJ, KMED, BATT, NETL, IBUY, SPAK, USMV, FDG and LQD.
State-owned electricity utility Eskom has issued a no-obligation request for information (RFI) in a bid to gain insight into what flue gas desulphurisation (FGD) technologies are currently available and to assess their potential suitability for deployment at the Medupi power station, in Limpopo. In a public notice, Eskom said the installation of FGD at Medupi by June 2025 formed part of a legal covenant with the World Bank, which loaned the South African utility $3.75-billion in 2010 largely for the purposes of building the 4 800-MW power station. The technology would be used to lower the coal-fired power plant’s sulphur dioxide (SO2) emissions in line with South Africa’s tightening minimum emissions standards. It has been widely reported that Eskom has been seeking to persuade the World Bank to allow it to pursue alternatives to the installation of FDG across Medupi’s six units, owing to the fact that the installation was expected to cost more than R40-billion and add to its already unsustainable debt burden. Eskom’s current debt stands at about R480-billion. The utility has also argued that retrofitting the units with FDG technology would dramatically increase the power station’s water consumption in a region that is already water stressed. Eskom said the RFI responses, which should be delivered to it by November 3, would be used to assist it in further developing its strategy for reducing SO2 emissions at Medupi. Consideration could also be given to using the technologies outlined at other coal stations in the utility’s generation fleet. “Eskom is currently in pursuit of the latest available information on the FGD technologies that will enable compliance to the relevant environmental legislation in a cost-effective and timeous manner, whilst being cognizant of the requirement for water conservation,” the RFI documentation states. Respondents could suggest more than one FGD technology option, provided that the specific limits that each technology was capable of achieving were outlined, along with the costs. The baseline unabated SO2 emissions for reduction were stated as being 4 367.03 milligrams per cubic metre (mg/Nm3). The current limit for Medupi was 3 500 mg/Nm3 and, by 2025, the limit would be 1 000 mg/Nm3. Eskom said submissions should aim to provide technology solutions to meet an emission limit of 200 mg/Nm3.
Pour cet épisode estival, Fin Du Game ouvre une faille spatio-temporelle et retourne en 1998 à Black Mesa, pour aller au bout d'Half-Life. A cette époque, les FPS sont encore des Doom/Quake-Likes et 2 anciens de Microsoft veulent rafraichir le genre. Gabe Newell et Mark Harrington fondent Valve et s'entourent de talents pour créer un shooter qui deviendra beaucoup plus que ça. Car si l'aventure de Gordon Freeman comporte de nombreuses fusillades réussies, c'est aussi son univers inspiré, sa narration avant-gardiste et ses mises en jeu toujours surprenantes qui la feront entrer dans la légende du medium. Et son pied-de-biche, évidemment. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.08.192872v1?rss=1 Authors: Viswanath P. Sudarshan, Shenpeng Li, Sharna D. Jamadar, Gary F. Egan, Suyash P. Awate, Zhaolin Chen Abstract: Functional positron emission tomography (fPET) imaging using continuous infusion of [18F]-fluorodeoxyglucose (FDG) is a novel neuroimaging technique to track dynamic glucose utilization in the brain. In comparison to conventional static PET, fPET maintains a sustained supply of glucose in the blood plasma which improves sensitivity to measure dynamic glucose changes in the brain, and enables mapping of dynamic brain activity in task-based and resting-state fPET studies. However, there is a trade-off between temporal resolution and spatial noise due to the low concentration of FDG and the limited sensitivity of multi-ring PET scanners. Images from fPET studies suffer from partial volume errors and residual scatter noise that may cause the cerebral metabolic functional maps to be biased. Gaussian smoothing filters used to denoise the fPET images are suboptimal, as they introduce additional partial volume errors. In this work, a post-processing framework based on a magnetic resonance (MR) Bowsher-like prior was used to improve the spatial and temporal signal to noise characteristics of the fPET images. The performance of the MR guided method was compared with conventional Gaussian filtering using both simulated and in vivo task fPET datasets. The results demonstrate that the MR guided fPET framework reduces the partial volume errors, enhances the sensitivity of identifying brain activation, and improves the anatomical accuracy for mapping changes of brain metabolism in response to a visual stimulation task. The framework extends the use of functional PET to investigate the dynamics of brain metabolic responses for faster presentation of brain activation tasks, and for applications in low dose PET imaging.Competing Interest StatementThe authors have declared no competing interest.View Full Text Copy rights belong to original authors. Visit the link for more info
Entre l'essai, la blague et la méta-fiction, The Stanley Parable est peut-être le jeu le plus atypique sur lequel Fin Du Game est revenu. Il nous enferme dans un dialogue interactif avec un narrateur sarcastique auquel on pourra choisir d'obéir ou non. Et si les nombreuses fins qui découlent de ces choix peuvent sembler très différentes les unes des autres, elles nourrissent toutes une même réflexion sur la liberté et les contraintes que nous offrent les jeux vidéo. 7 ans après sa sortie finale, le jeu de Davey Wreden et William Pugh est toujours aussi pertinent. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.136838v1?rss=1 Authors: Meadowcroft, M. D., Purnell, C. J., Wang, J.-L., Karunanayaka, P., Yang, Q. Abstract: Cerebellar involvement in Alzheimers disease (AD) has not been studied to the extent that cortical neuropathological changes have. Historical and recent histopathological literature demonstrate cerebellar AD pathology while functional investigation has demonstrated disrupted intrinsic cortical-cerebellar connectivity in AD. Additionally, olfactory deficits occur early in AD, prior to the onset of clinical symptoms. The neurological basis for the involvement of the cerebellum and olfactory system in the disease course remain unclear. 18F-fludeoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimers Disease Neuroimaging Initiative (ADNI) were analyzed to characterize metabolism in the cerebellum and olfactory region of AD, mild-cognitive impaired (MCI), and age-matched cognitively normal (CN) controls. In contrast to known parietal and temporal lobe FDG hypo-metabolism within the default mode network in AD, a significant FDG hyper-metabolism was found in the cerebellum and olfactory cortical regions (including the piriform cortex, olfactory tubercle, anterior olfactory nucleus, and nucleus accumbens shell). The increase in cerebellum glucose utilization was shown also in late- verses early-MCI patients. The cerebellar and olfactory regions both contain inhibitory distal and inter-neuronal connections that are vulnerable to disruption in AD. The hyper-metabolism in the cerebellum and olfactory structures may reflect disruption of local and system-wide inhibitory networks due to AD neurodegeneration, suggesting a hypothetical mechanism for susceptibility of the olfactory system to early AD pathology. Copy rights belong to original authors. Visit the link for more info
Far Cry 3 marque une étape importante pour Ubisoft. Après avoir imposé sa formule du monde ouvert avec Assassin's Creed, la firme des Guillemots va chercher à la décliner sur d'autres typologies de jeu, notamment le FPS. Et le pari est réussi. Une île paradisiaque, un vilain charismatique et une myriade d'activités secondaires, le jeu s'impose comme LE shooter pop-corn de 2012. Et même si l'auteur du jeu aurait aimé qu'on y voit plus que ça, c'est bien ce fun très premier degré qui deviendra la marque de la série, avant qu'elle finisse par tourner en rond, comme beaucoup d'autres séries de l'éditeur. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Dès ses premières apparitions, GRIS se fait remarquer par sa direction artistique hors-norme. Il la doit à son créateur, Conrad Roset, un illustrateur espagnol déjà bien installé, qui s'est lancé dans la création de jeu vidéo après une rencontre avec 2 anciens d'Ubisoft en 2015. Nomada Studio nous invite donc à redonner vie au monde brisé d'une jeune femme, où chaque nouvelle couleur qui s'ajoute et se mélange aux autres est un pas de plus vers la reconstruction. C'est une expérience onirique d'une fluidité exquise, mais qui peine parfois à dépasser ses références, ludiques ou thématiques. Fin Du Game fait son vernissage dans ce nouvel épisode. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.08.084293v1?rss=1 Authors: Zhuo, J., Zhang, Y., Liu, B., Liu, Y., Zhou, X., Bartlett, P. F., Jiang, T., the ADNI Abstract: The failure of all anti-amyloid-{beta} (A{beta}) drugs has led to a debate about the central role of amyloid in sporadic Alzheimer's disease (SAD). In order to resolve this issue, it is necessary to evaluate the impact of A{beta} biomarkers on SAD by measuring the dynamic changes in biomarkers and clinical profiles in the progression of SAD. We identified a clearer picture of the clinical and biomarker changes in the progression of SAD by aligning the clinical diagnosis of mild cognitive impairment (MCI) or AD onset. We found that changes in hippocampal volume and FDG, rather than A{beta} biomarkers, were associated with the changes in clinical measures in the progression of SAD. In addition, cognitively normal people with elevated and with normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG. This study reveals that A{beta} is not a useful biomarker for predicting the clinical progression of patients who develop SAD. Copy rights belong to original authors. Visit the link for more info
Est-ce que le démons peuvent pleurer ? La question reste ouverte mais ce qui est sûr, c'est qu'ils savent se battre avec style. Après une pause de plus de 10 ans pour la série, Hideaki Itsuno et son équipe ont pouvé que Devil May Cry avait encore sa place dans l'ère moderne. Ce 5ème épisode est une démonstration de leur expertise du jeu d'action à la japonaise, celui où l'animation est reine et chaque nuance de gameplay est un outil d'expression pour celui ou celle qui tient la manette. Le tout servi par un trio de personnalités fortes et complémentaires, qui ne laisse jamais tomber le rythme de l'aventure. Appuyez sur le Devil Trigger, c'est parti pour un nouvel épisode de Fin Du Game. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Our guest today is Dr. Francisco Gonzalez-Lima, a professor in the department of psychology, pharmacology and toxicology and the department of psychiatry at The University of Texas at Austin. He also is a professor at the university’s Institute for Neuroscience. We covered so much ground in our discussion with Francisco that we have split his interview into two parts. Today’s interview focuses on Francisco’s fascinating background as a youth and Cuban expatriate as well as his early research into Alzheimer’s Disease and brain metabolic mapping. The second part of our interview, which follows in a few weeks, covers two interventions Francisco has been exploring with the aim of protecting people against neurodegeneration: low-dose methylene blue and the application of near-infrared light. Francisco describes himself as a behavioral neuroscientist. He and his colleagues at the Gonzalez-Lima Lab are recognized as world leaders for their research on the relationship between brain energy metabolism, memory and neurobehavioral disorders. Although he has spent most of his academic career at the University of Texas, Francisco has been a visiting neuroscientist in Germany, England, Canada and Spain, and has delivered more than 120 lectures around the world about his brain research. He also has contributed work to more than 300 scientific publications. Over the years, Francisco’s brain research has focused on transcranial lasers, memory enhancement, neuroprotection and neurocognitive disorders. Current research in the Gonzalez-Lima laboratory focuses on the beneficial neurocognitive and emotional effects of noninvasive human brain stimulation in healthy, aging and mentally ill populations. This research primarily uses transcranial infrared laser stimulation and multimodal imaging. Show notes: [00:03:23] Dawn opens the interview mentioning that Francisco was born in Cuba where his father worked as a veterinarian. Dawn asks how Francisco’s family ended up leaving Cuba for Costa Rica when he was only ten years old. [00:04:25] Ken asks if it is true that Francisco got into a lot of fights as a child. [00:05:19] Francisco talks about his time as a child accompanying his veterinarian father to take care of cattle. [00:06:46] Dawn asks about Francisco’s time in college, two years of which he spent in Venezuela, and how he became known as an anti-communist student leader on campus. [00:08:18] Francisco tells the story of how he ended up going to school at Tulane University. [00:09:13] Dawn mentions that because Francisco’s father was a veterinarian, Francisco went to Tulane with the intent of working with animals. But after watching a professor dissect a human brain in class one day, Francisco changed his major. [00:10:17] Ken asks Francisco what lead him to decide to get a bachelor’s degree in biology and psychology. [00:11:49] Dawn asks about Francisco’s work with Nobel Prize winner Dr. Andrew Schalley during Francisco’s last summer at Tulane. [00:12:56] Francisco explains how he ended up of the University of Puerto Rico getting his doctorate in anatomy and neurobiology. [00:14:28] Dawn asks Francisco how learning about electrophysiology in his doctoral studies had an impact on him. [00:15:22] Francisco tells an interesting story of his doctoral dissertation. [00:16:21] Dawn asks about Francisco’s work with Dr. Walter Stiehl and the papers the two of them published in the European Journal of Pharmacology. [00:17:19] Dawn mentions that in 1981 Francisco met Henning Scheich, a German professor who had done a study involving the newly developed 2-deoxyglucose autoradiographic method. Francisco talks about why this neuroimaging approach to brain research fascinated him and led him to propose an ambitious collaborative research project with Dr. Scheich. [00:18:27] Dawn asks Francisco to talk about the work he did with Dr. Scheich to develop the human FDG (fluorodeoxyglucose) neuroimaging m...
We thought Jordan was the perfect guest to roll out new segments with! Jordan and his wife Katie have been building Final Drive Genetics at a rapid success rate. We talk about the history of starting FDG with one sow among his father having untraditional show livestock background. We answer questions like; Is the market flooded with "those one sow operations"? What's it like moving a sow herd from Indiana to Arkansas? $1000 Scholarship: https://stocktalk-podcast.com/stock-talk-podcast-scholarship/The Showman - Showmanship Contest: https://www.facebook.com/482290585617317/videos/515547992665099/Support the show (https://www.facebook.com/TheStockTalkPodcast/?modal=admin_todo_tour)
Héritier direct d'Alien: Isolation, Observation reprend à son compte l'exercice du huis-clos spatial, en apportant un twist inédit : nous faire incarner l'intelligence artificielle qui règne sur les systèmes et l'administration de la station. En adoptant cette perspective, en nous faisant jouer avec les interfaces et les caméras, le studio NoCode nous plonge dans un thriller certes référencé, mais qui ne pouvait être raconté que dans un jeu vidéo. Direction Saturne pour un nouvel épisode de Fin Du game, ECOUTEZ-LE. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
This week’s episode will examine data on the impact of the FDG uptake level on predicting subsequent high-grade histological transformation in follicular lymphoma, explore clonal tracking in gene therapy patients as a method for understanding human hematopoiesis, and review a study on the recognition of platelet factor 4-von Willebrand factor complexes by heparin-induced thrombocytopenia antibodies as a basis for the pathogenesis of HIT.
Après 2 premiers épisodes qui leur avaient permis de s'imposer dans la sphère des jeux de rôles occidentaux, les équipes de CD Projekt voulaient passer un nouveau cap The Witcher 3.Un monde vaste et foisonnant, des quêtes qui s'entremêlent et arrivent à nous impliquer dans des choix nuancés, des personnages charismatiques et attachants... L'ambition était démesurée et pourtant, elle s'est bien concrétisée.Et si tout n'est pas parfait, 5 ans après sa sortie, il est encore difficile de trouver un jeu pouvant tenir tête au champion polonais dans la catégorie Action-RPG en open world. Jusqu'à Cyberpunk 2077 ? Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
This week! It’s the seven HUNDREDTH podcast. We take a trip down memory lane of the podcast and when the hosts first met up, then we discuss delays, April Fools jokes, Animal Crossing, Cooking Mama weirdness, and much, much, more. Join us, won’t you? Links of interest: Phil’s first episode of Player One Dr. Smith “Special Guest” Shawnimals Rumor: Multiple Mario remasters coming for Switch Quackshot April Fool tweet FDG explains it was a failed pitch Last of Us Part II and Iron Man VR delayed indefinitely Rogue Legacy 2 announced IGN to host Summer of Gaming event Extra Life United digital tournament event Corona Relief Done Quick Resident Evil 8 rumored to hit next year Animal Crossing New Horizons Pirates of Barracuda Bay Funny Farm sheep’s balls Space Quest 3 Snakeybus Cooking Mama Cookstar Cooking Mama dev shuts down rumours of Switch version mining cryptocurrency The Cooking Mama Game for Switch That Came Out, and Then Disappeared Al Lowe interview episode Ted Woolsey interview episode Episode 666 First Dormerbot episode Wii/PS3 launch episode Greg Sewart’s Extra Life Page Greg’s Out of the Park Developments stream The Player One Podcast t-shirt The Player One Podcast mug ResetEra Player One Podcast Topic Player One Podcast Discord Greg Streams on Twitch Flicky - Generation 16 Episode #120 Add us in Apple Podcasts Check out Greg's web series Generation 16 - click here. And take a trip over to Phil's YouTube Channel to see some awesome retro game vids. Follow us on twitter at twitter.com/p1podcast. Thanks for listening! Don't forget to visit our new web site at www.playeronepodcast.com. Running time: 02:10:35
Paul J. Wang: Welcome to the monthly podcast On the Beat for Circulation: Arrhythmia and Electrophysiology. I'm Dr Paul Wang, Editor-in-Chief with some of the key highlights from this month's issue. In our first paper, Jacob Koruth and Associates examine the ability to produce ablation lesions using pulse field ablation, which is tissue specific and non-thermal in swine compared to radio frequency ablation. All 46 targeted veins were successfully isolated on the first attempt in all cohorts. Pulmonary vein isolation durability was assessed in 28 veins, including the SVC. Durability was higher in the pulsed field ablation bipolar group, 18 out of 20 in the bipolar group, 10 out of 18 in the monopolar group, and 3 out of 6 in the radio frequency group. P = 0.002. Transmit morality rates were similar across groups with evidence of nerve damage only with radiofrequency. In our next paper, Vivek Reddy and Associates is part of the multicentered first-in-human study, RADIANCE, examine the ability of a novel compliant radio frequency balloon catheter with 10 irrigated flexible electrodes to simultaneously and independently deliver energy. At four sites, 39 patients with paroxysmal atrial fibrillation underwent pulmonary vein isolation using energy delivery simultaneously from all electrodes up to 30 seconds posteriorly, and 60 seconds anteriorly. 152 of 152 targeted pulmonary veins were isolated. 79.6% with a single application. Electrical reconnection occurred in only 7 out of 150 pulmonary veins or 4.7% upon adenosine isoproterenol challenge. Esophageal temperature was monitored in all patients. The esophagus was also mechanically deviated in ten patients. At three months, imaging revealed no pulmonary vein stenosis and early atrial recurrence occurred in only 10 out of 39 or 25.6% of patients. In our next paper Takeshi Kitamura and Associates examine the effect of substrate based ventricular tachycardia ablation targeting local abnormal ventricular activity on recurrent ventricular fibrillation events in patients with structural heart disease. In a retrospective two center study of a total of 686 patients with incident ventricular tachycardia ablation procedure targeting local abnormal ventricular activity, 21 patients, age 57 years left ventricular ejection fraction 30%, had both ventricular tachycardia and ventricular fibrillation. A total of 80 ventricular fibrillation events were recorded in the ICD logs, the six months preceding ablation. Complete and partial local abnormal ventricular activity elimination was achieved in 11 or 52%, in 10 or 58% of patients respectively. Catheter ablation was associated with a highly significant reduction in ventricular fibrillation recurrences. P less than 0.0001 which were limited to three or 14 patients at six months. The total number of ventricular events therefore, decreased from 80 to three with a median of 1.0 to 0.0 in the six months prior to and following ablation respectively. The reduction in ventricular fibrillation events was significantly greater in patients with catheter ablation compared to 21 match controls during a 6- month period preceding and following a baseline assessment. The authors concluded that substrate guided ventricular tachycardia ablation, targeting local abnormal ventricular activity, may be associated with a significant reduction in recurrent ventricular fibrillation, suggesting that ventricular tachycardia and ventricular fibrillation share overlapping arrhythmogenic substrate in patients with structural heart disease. In our next paper, Feng Hu and Associates examine the effect of right anterior ganglion aided plexi ablation on vagal response during circumferential pulmonary vein isolation. 80 patients with paroxysmal atrial fibrillation who underwent first time ablation were prospectively enrolled and randomly assigned to two groups. Group A (n = 40) circumferential pulmonary vein isolation starting with the right pulmonary veins at the right anterior ganglion plexi site. In group B (n = 40) circumferential pulmonary vein isolation starting with the left pulmonary veins first, and the last ablation site being the right anterior ganglionic plexi site. During circumferential pulmonary vein isolation, the positive vagal response was observed in only one patient in group A, in 25 patients in group B. P less than 0.001. A total of 21 patients with positive vagal response in group B needed temporary ventricular pacing during the procedure, while the only patient with positive vagal response in group A did not need temporary ventricular pacing, P less than 0.001. Compared with baseline basic cycle length, sinus node recovery time, and AV node Wenckebach pacing cycle length were decreased significantly after pulmonary vein isolation procedure in both groups, all P less than 0.05 and without differences between the two groups. In our next paper, Karl-Heinz Kuck and Associates reported the results of the randomized atrial fibrillation management and congestive heart failure with ablation, AMICA trial. Patients with persistent or long standing persistent atrial fibrillation and left ventricular ejection fraction ≤ 35%, were randomly allocated to catheter ablation of atrial fibrillation or best medical therapy. The primary study endpoint was the absolute increase in left ventricular ejection fraction from baseline at one year. Pulmonary vein isolation was the primary ablation approach. Best medical therapy comprised rate or rhythm control. All patients were discharged after index hospitalization with a cardioverter defibrillator or resynchronization therapy defibrillator implanted. This study was terminated early for futility of 140 patients, 65 years, 90% men available for endpoint analysis, 68 and 72 patients were assigned to ablation in best medical therapy respectively. At one year, left ventricular ejection fraction had increased in ablation patients by 8.8% and in medical therapy by 7.3%, P = 0.36. Sinus rhythm was recorded on 12-lead electrocardiograms at 1 year. In 61 of 83 ablation patients, or 73.5%, and 42 out of 82 best medical therapy patients or 50%. Device-recorded atrial fibrillation at one year, was 0% or maximally 50% of the time in 28 of 39 ablation patients, so 72% in 16 out of 36 best medical therapy patients or 44%. There were no differences in secondary endpoint outcomes of six-minute walk tests, quality of life or NT pro BNP between the ablation and best medical therapy patients. In our next paper, Dhanunjaya Lakkireddy and Associates examined the association between unrecognized inflammation and premature ventricular contraction. In a single-center prospective study, 107 patients with 5,000 or more PVCs per 24 hours, which were symptomatic, and no known ischemic heart disease, underwent combination of laboratory testing including FDG or 18F-fluorodeoxyglucose pet scan, cardiac magnetic resonance imaging, and biopsy. The mean age cohort was 57 years, 41% were males, a left ventricular ejection fraction was 47%. Positive pet scan was seen in 51%, and 51% had preserved left ventricular function. Based on clinical profile, FDG pet imaging, cardiac magnetic resonance imaging, and histological data, 58% received immunosuppressive therapy alone and 25% received immunosuppressive therapy and catheter ablation. Optimal response was seen in 67% over a mean follow-up of six months in patients with left ventricular systolic dysfunction, 37% showed a mean improvement in left ventricular ejection fraction of 13%. In our next paper, Clare Atzema and Associates examined the association of rapid (3 days), early (7 days), and basic (30 days), outpatient physician follow-up with short and long-term outcomes in atrial fibrillation patients discharged from an emergency department. In 163 emergency departments in Ontario, Canada with a diagnosis of atrial fibrillation, they use landmark analysis with propensity score matching. In the 10,657 patients with rapid follow-up care who are propensity score matched to a patient with follow-up between 4 and 7 days, the hazard of a return emergency visit was reduced by 11%. In the 17,234 patients with early follow-up who are matched to a patient with care between 8 and 30 days, the 1-year mortality was 11% lower, and 1-year hospitalization was 6% lower. Relative to no 30-day care, basic follow-up care was associated with an increased hazard ratio of 90-day hospitalization, but no longer was associated with mortality. The authors concluded that compared to follow-up care between 8 and 30 days, follow-up care within a week after discharge from an emergency department with atrial fibrillation, was associated with a reduction in death, in hospitalization at 1 year, in association not present with 30-day follow-up. In our next paper, James Freeman and Associates evaluate outcomes including death, myocardial infarction, stroke or systemic embolism, intracranial bleeding, major bleeding hospitalization in patients undergoing atrial fibrillation ablation compared with a propensity score match cohort of patients treated with anti-arrhythmic medications only in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) I and II registries. Among 21,595 patients, 6% underwent de novo atrial fibrillation ablation. The propensity score matched cohort included 1087 patients who underwent atrial fibrillation matched one-to-one with 1087 patients treated with an antiarrhythmic medication only. There were no significant differences in the risk of all-cause and cardiovascular death in most other major cardiovascular and neurologic events. Atrial fibrillation catheter ablation was associated with an increased risk of all cause hospitalization hazard ratio 1.24 particularly in the 3 months after the procedure. Among those who underwent atrial relation ablation with CHA2DS2 VAS score, 2 for men and 3 for women, 23% had oral anticoagulation discontinued after ablation. Among those with discontinue oral anticoagulation, the median time to discontinuation was 6.2 months. Thus, the authors found no difference in adjusted rates of cardiovascular and all-cause death, between patients treated with atrial fibrillation catheter ablation and antiarrhythmic medications only. In our next paper, Michael Liu and Associates examined R-from-T as a common mechanism of arrhythmia initiation in long QT syndrome. In their study, spontaneous initiation of polymorphic ventricular tachycardia was elicited by gradually ramping up ICa,L to simulate the early phase of sympathetic surge or changing the heart rate, reproducing the different genotype-dependent clinical electrocardiographic features in LQTS type 2 and 3, T-wave alternans was observed followed by premature ventricular complexes. Compensatory pauses occurred resulting in short-long sequences, as ICa,L increased further polymorphic ventricular tachycardia episodes occurred, always proceeded by short-long-short sequences. However, in LQTS type 1 once a PVC occurred, it almost immediately led to an episode of polymorphic ventricular tachycardia. Arrhythmias in LQT2 and 3 were bradycardia dependent, whereas LQT1 was not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. the authors called this mechanism R-on-T to distinguish it from the classic explanation of R-on-T arrhythmogenesis when an exogenous PVC coincidentally encounters a repolarization region. In R-from-T, the PVC and the T wave are causally related, where the steep repolarization gradients combine with enhanced ICa,L leading to the PVCs emerging from the T wave. Since enhanced ICa,L was required for R-from-T to occur, suppressing window ICa,L effectively prevented arrhythmias in all 3 genotypes. In our next paper, Dhani Dharmaprani and Associates hypothesized phase singularity formation and destruction in fibrillation could be modeled as a self-regenerating Poisson renewal processes, producing exponential distributions of inter event times governed by constant rate parameters defined by prevailing properties of each system. The authors studied 5 systems, human persistent atrial fibrillation in 20 cases, tachypaced atrial fibrillation in sheep in 5 cases, rat atrial fibrillation in 4 cases, and rat ventricular fibrillation in 11 cases, as well as computer simulated fibrillation. Phase singularity time to event data were fitted by exponential probability distribution functions computed using maximum entropy theory, and rates of phase singularity formation and destruction were determined. A systematic review is conducted to cross validate with sources from the literature. In all systems phase singularity lifetime and inter formation times were consistent with underlying Poisson renewal processes. The authors conclude that Poisson renewal theory provides an evolutionarily preserved universal framework to quantify formation and destruction of rotational events in cardiac fibrillation. In our issue, there was a very interesting special report on hypothermia outcomes after transvenous lead extraction complications requiring cardiothoracic surgery by Peter Hu and Associates. In addition, there is a very interesting review of atrial fibrillation mediated cardiomyopathy by Kevin Heist and Associates. That's it for this month. We hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next time. This program is copyright American Heart Association 2019.
SuperGiant Games fait partie de ces studios qui ont émergé avec les Summers Of Arcade du Xbox Live, berceau du jeu vidéo indépendant moderne. Après le succès surprise de Bastion, l'équipe américaine a eu du mal à trouver son second projet, paralysée par l'envie de surprendre et de ne pas décevoir. Il en est ressorti Transistor, un titre au charisme indéniable, notamment grâce à ses visuels et sa bande-son, mais aussi un peu bancal, où les nombreux combats peinent à garder leur intérêt malgré toutes les combinaisons qu'ils nous offrent. Quelques fausses notes qui n'empêchent pas Fin Du Game de revenir avec plaisir sur la quête vengeresse de Red. Episode enregistré à distance, confinement Covid-19 oblige. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Summary: 1. How functional imaging is different from anatomic imaging 2. Different tracers - FDG, NAF, DOTATATE, AXUMIN, PSMA 3. Limitations (size, lack of contrast in some places) 4. Pitfalls - know expected physiologic uptake and other processes that cause uptake 5. Future of PET - exciting implications for therapies Host: Christopher Cerniglia, DO, ME, FAOCR. Associate Professor of Radiology, Division of Musculoskeletal Imaging & Intervention, UMMS Dept of Radiology. Guest: Lacey J McIntosh DO, MPH. Assistant Professor of Radiology, Divisions of Abdominal Imaging and Nuclear Medicine, UMMS Dept of Radiology. Resources: 1. Kapoor, V., McCook, B. M., & Torok, F. S. (2004). An introduction to PET-CT imaging. Radiographics, 24(2), 523-543.. 2. Bar-Shalom, R., Valdivia, A. Y., & Blaufox, M. D. (2000, July). PET imaging in oncology. In Seminars in nuclear medicine (Vol. 30, No. 3, pp. 150-185). WB Saunders. 3. Wallitt, K., Yusuf, S., Soneji, N., Khan, S. R., Win, Z., & Barwick, T. D. (2018). PET/CT in Oncologic Imaging of Nodal Disease: Pearls and Pitfalls: RadioGraphics Fundamentals| Online Presentation. RadioGraphics, 38(2), 564-565. 4. Wang, G. X., Kurra, V., Gainor, J. F., Sullivan, R. J., Flaherty, K. T., Lee, S. I., & Fintelmann, F. J. (2017). Immune checkpoint inhibitor cancer therapy: spectrum of imaging findings. Radiographics, 37(7), 2132-2144.
Malgré sa taille et son ancienneté, le studio Asobo reste peu connu du grand public. A Plague Tale : Innocence est clairement là pour changer ça. En s'inspirant des champions de la narration par l'action que sont Naughty Dog, les bordelais ont tenté de percer sur le marché du "double-A" avec une aventure mature mais accessible. Une histoire de famille dans un moyen-âge pestilent où les rats grouillent et les cadavres s'entassent. Est-ce une réussite ? Réponse dans ce nouvel épisode. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Des masques d'animaux. Des battes de base-ball. Des mafieux et des dance-floors ensanglantés. Non, Hotline Miami ne fait pas partie de ces titres qui donnent une bonne image du jeu vidéo au grand public. Et pourtant, tout le génie du jeu de Dennaton Games réside dans sa façon de transcender la violence, par sa musique electro-punk et sa boucle hypnotique. C'est un petit cacheton d'adrénaline pure, repéré par Devolver et finalement devenu mascotte du jeu vidéo indé au début des années 2010. C'est reparti pour un trip. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Avec la sortie de cette première saison de The Walking Dead, Telltale Games a provoqué une petite détonation dans l'industrie. Alors qu'on croyait le point & click condamné à une niche de nostalgiques, le studio fondé par quelques anciens de Lucas Art a ouvert une nouvelle voie au genre et renoué avec le succès populaire. Gestions des conflits, résolutions de problèmes, un peu de fouille et d'action, l'univers des The Walking Dead collait parfaitement à cette nouvelle formule basée sur des choix moraux et des cliffhangers. Et la sauce a bien pris. Si bien même que le studio va par la suite s'embourber dans sa propre recette, trop occupé à la décliner pour la voir s’essouffler... Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Tracer des lignes sur quelques 500 panneaux. Ce n'est pas vendeur pour un rond et pourtant, c'est bien ce que nous demande de faire The Witness. Après le succès de Braid, Jonathan Blow a fait tapis en réinvestissant tous ses gains (et plus encore) dans la création d'une île remplie de puzzles. Mais en s'entourant d'artistes et d'architectes, il a pu façonner un microcosme aussi complexe que coloré. Un espace propice à l'apprentissage, la réflexion et peut-être même l'épiphanie. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Comment mieux commencer 2020 qu'avec Bioshock ? Rapture, les Big Daddies, Andrew Ryan... L'univers imaginé par Ken Levine et son équipe a marqué le jeu vidéo et reste une de ses références les plus nobles. Et même si certains aspects de sa proposition peuvent paraitre archaïques aujourd'hui, on peut y déceler de nombreux traits de design qui ont dessiné le AAA dans la dizaine d'années qui ont suivi sa sortie. Il était donc temps pour Fin Du Game de s'y replonger. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Comment mieux terminer 2019 qu'avec Outer Wilds ? C'est vrai, c'est un amalgame étonnant : exploration spatiale, balade forestière, physique quantique, marshmallows... Il y aurait 1000 raisons pour que ça ne fonctionne pas et pourtant, il tourne. Par sa richesse et l'autonomie qu'il nous donne, le jeu de Mobius Digital donne un nouveau sens à la découverte et atterrit tout en haut de notre panthéon annuel. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Pour fêter son premier anniversaire, Fin Du Game revient sur un des titres les plus marquants de la décennie : UNDERTALE. Derrière son esthétique modeste et ses airs de JRPG sortis tout droit des années 90, le jeu de Toby Fox est en réalité une réflexion ambitieuse sur la confrontation et l'empathie dans la vie comme le jeu vidéo. Un conte ludique qui n'oublie pas de nous rappeler que toutes nos actions ont des conséquences. Ah et puis la musique déchire. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Shlomo Koyfman from the Cleveland Clinic, lead author on "Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Koyfman. It's a pleasure. So first, can you give us a general overview of what this guideline covers? Yeah, so this is an exciting guideline because it covers a topic that we don't usually think about in head and neck cancer in a formal way, and that is management of the neck in squamous cell cancer of the oral cavity and the oropharynx. So there's a lot of literature and guidelines out there on how to manage oropharynx cancer, which is becoming a more and more common cancer, especially in the HPV-positive era, less so on oral cavity. But a lot of times it's focused on people who don't get surgery, chemoradiation, or people who do get surgery and TORS, Transoral Robotic Surgery, and different approaches. But rarely do we have something focus on management of the neck per se, which is really, really important in these cancers and often overlooked in favor of the primary tumor itself. So these guidelines really take us through some salient questions in how to manage the neck in these two cancers. And what are the key recommendations of this guideline? The recommendations came off of six fundamental questions, three in oral cavity and three in oropharynx. There are some commonalities between the two and some differences. A lot of the fundamental questions revolve around surgical quality, and neck dissection is the standard surgical approach for management of the neck in these patients. And as we enter the quality era, how do we define benchmarks of surgical quality, which is one thing that it deals with. The other is when to do adjuvant therapy like adjuvant radiation or chemoradiation. We also deal with when to do surgery for the neck or to do nonoperative approaches like radiation or chemoradiation. And then lastly, how do you follow patients after you've treated them? So those are kind of the salient issues that we dealt with. And what we came out with was nothing earth shatteringly new, but I think the way it was organized and systematically put together, I think it's going to be really, really helpful for people. So some of the most important findings that this recommendation does, I think this is the first that incorporates surgical quality, as I mentioned before. So specifically neck dissection should have 18 or more nodes as multiple studies have shown that that's associated with better outcomes. And similarly we define for different diseases of oral cavity and oropharynx, and depending on what kind of tumor it is and where, what nodal levels should be dissected or treated, whether surgically or nonsurgically, and when to do just one side of the neck versus both sides of the neck. So I think there's a lot of good guidance there in terms of the surgical quality. From a standpoint of adjuvant therapy, we define pretty clearly indications for when after surgery for oral cavity cancer, for example, when radiation should be added and when chemoradiation should be added, and I think that's very helpful. And especially for the neck itself, there's been confusion about what happens if I have 30 nodes taken out and they're all negative but I have a big, large primary tumor. What do I do with the neck? Do I radiate it? Do I not radiate it at one side, both sides? And this guideline gives some pretty clear guidance in different scenarios about how to think about that, which is pretty novel and really important, I think. I get questions about this all the time. It comes up in tumor boards all the time, and it's pretty practical. And mostly what we say is if you have a primary tumor that's like a T3 or T4 oral cavity cancer or it approaches midline, either a contralateral neck dissection should be done or radiation should be done to the contralateral neck. And even if you have a lot of lymph nodes taken out and they're negative, if you have very high-risk primary tumor features like very large tumor or multifocal perineural invasion, those kinds of things, even with a negative neck dissection we still typically do treat the neck. So the next recommendation that's really helpful is who can be observed after surgery? And specifically low-volume N1 you can consider observing in oral cavity cancer, whereas N2 or N3 patients all need radiation or chemoradiation in the setting of extranodal extension and positive margins. We did come out pretty firmly advocating for bolus cisplatin 100 milligrams per meter squared every three weeks as recent studies suggest that weekly cisplatin or other regimens are not as effective, and we were pretty clear about that. We were pretty synchronized with recent ASCO-endorsed guidelines in oropharynx cancer that say similar things. In addition, one of the very important questions that comes up is a surgeon will say, well, I'm cutting out the neck tumor, and I know it comes to midline and he's got a bunch of nodes on the right side, but do I really need to do a left neck dissection? Aren't you going to radiate it anyway? And that comes up all the time. Is radiation adequate to manage a clinically negative neck in oral cavity cancer and oropharynx cancer? I think in oropharynx cancer everybody feels pretty comfortably yes. I think in oral cavity cancer it's been somewhat controversial. We favor neck dissections when possible, but if radiation is known to be happening, especially to an elective contralateral neck, that that is adequate therapy. However, we're pretty strong in the fact that neck dissections are the tried and true way to treat oral cavity cancer and that in a T2 or above tumor where a neck dissection is indicated, just resecting the primary and leaving the neck to elective radiation is not something that we thought there was enough evidence for to advocate, and we still advocate classic neck dissection first followed by adjuvant radiotherapy as indicated. One area of controversy that we did touch on is the issue of early stage tongue cancers and whether they need a neck dissection at all. And we came down pretty consistently with all of the co-authors on the guideline that we advocated for a neck dissection for all patients with oral cavity cancer unless it is a very small tumor that we define with very compliant patient who is amenable to very rigorous follow-up that has been done in Europe and in some other places with, specifically, people trained in careful neck ultrasound techniques. So all of those really help guide, both in early stage and more advanced stage, how to manage the neck and oral cavity cancer. And in oropharynx cancer, again, many of the same quality metrics apply. We have some guidance about when doing transoral robotic surgery how to reduce bleeding risk by ligating feeding blood vessels, which is an important addition. We also discuss the fact that, as opposed to lateralized oral cavity patients where a unilateral either neck dissection of radiation is often indicated, in oropharynx cancer the group felt very strongly that bilateral neck should be treated. And typically if tumors extend to midline or involve the posterior oropharyngeal wall, which has bilateral drainage, that either bilateral neck dissection should be performed in those cases or a unilateral neck dissection can be done as long as adjuvant radiation is planned to both necks. Finally, a couple of very important questions of who should not be treated surgically and who should be treated with a nonoperative chemoradiation based approach. In oral cavity cancer, as long as they were not metastatic, we felt people should be resected as long as they were surgically resectable and medically operable. In oropharynx cancer, however, anybody who had unequivocal extranodal extension of nodes into soft tissues or involvement to the carotid artery or extensive cranial-nerve involvement or skull-based involvement by extensive nodal disease are not good candidates for surgery and should be preferentially treated with chemoradiation. That was pretty strong. And finally, the other thing we gave clarity on is when we treat oropharynx cancer with chemoradiation, how do we follow them and when do we decide to do a neck dissection or not? And essentially we recommended a PET CT scan at 12 weeks. And as long as that was negative, a neck dissection should not be done. If you don't have a PET scan and you just have high quality CT or MRI but all of the neck disease has resolved, similarly there should be no neck dissection. And then most importantly, the situation we all face which is very complex is what happens when you have a PET CT done three to four months after treatment and you have small nodes that are still there? You have a little bit of uptake. The FDG avidity is much less than it was. There still is a lesion there, but it's much better and the patient is feeling well. And we felt pretty comfortable not doing a standard neck dissection on those patients but rather following them closely with a follow-up CT scan two to three months later and continual assessment and reserving surgery for obvious progressive disease. So why is this guideline so important, and how will it change practice? So this guideline is really important because head and neck cancer being not the most common cancer, and especially because head and neck cancer is not really one disease-- there's so many different diseases. Even oral cavity and oropharynx, there's quite a bit of variability in how we think about it. There's not a one size fits all recipe for how to manage people properly, and that leads to a lot of confusion and sometimes doubt as to what the best thing to do is in these patients. And that is a very common thing. So I think the most important reason why these guidelines are helpful is they're really clear. They give really clear guidelines of if you're going to do surgery, here's the expectations of what nodal levels to take out and how many nodes to take out. Here's when you should do adjuvant radiation. Here's when you should do adjuvant chemoradiation. Here's when you should treat one side of the neck. Here's when you should treat both sides of the neck. If you're not going to do surgery, here's when you do radiation. And for oropharynx cancer, here's when you can consider surgery. Here's where surgery is not the best idea. And when you treat them and if you do surgically, here's how you do it. If you do with radiation, here are the nodes that should be treated, the nodal levels. And finally, after you do that, how do you watch and act to make sure that people don't fail? So I feel like all of those things lend a lot of clarity to some complicated decision-making processes for these patients, and this really lends clarity to that, which should help kind of lend consistency of practice. That's really our goal. Our goal was there a lot of great docs taking care of these patients out there, but patients are treated in very different ways depending on who they're seeing and where you go. Our goal was to try to increase the consistency of how people are treated no matter where they are. And if practitioners, surgeons, radiation oncologists, medical oncologists see this guideline and kind of follow it and, of course, reach out with any questions at any time, then what we'll be able to do is kind of harmonize the way patients are treated in this country, which should help, I think, the quality of care. And finally, how will these guideline recommendations affect patients? They're going to affect patients because right now a lot of patients get great care, but there are some patients that are not getting ideal care either because maybe they're in parts of the country that don't have the same access to resources or they're in places where the volume of these kind of very complicated and yet not so common diseases aren't seen as high and there's confusion about how to manage them or what the quality metrics are. I think patients are going to be affected knowing, hey, if I'm going to have a neck dissection, here's what I should be asking to make sure my surgeon knows to do and does consistently to make sure it's of high quality. Here's where I think I should be treated with surgery, maybe I shouldn't be treated with surgery, and here's how to follow me. Because there is a lot of variability in how patients are treated, and sometimes there's too many surgeries being done, not enough surgeries being done. If they're being done, maybe they're not the best quality. Even if we don't treat with surgery and we do chemoradiation, we're watching them and we may not be following them as closely, and then people may be recurring and we're not picking it up closely enough. So I think it's going to harmonize, for patients, the way they're ultimately treated. If everybody in the country is treated relatively compatible with this guideline, I think the standard of care will go up across the board. Great. Thank you so much for your work on this important guideline, and thank you for your time today, Dr. Koyfman. Thank you so much. And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.
Sacré premier rencard pour Leon et Claire ! Comme l'orignal sorti en 1998, ce Remake de RE2 nous envoie tout droit dans le commissariat de Raccoon City pour tenter d'échapper à des zombies qui ont la dalle. Mais les équipes de Capcom ont du repenser leur recette pour cette fournée de 2019 : tenter de conserver les saveurs traditionnelles du survival-horror tout en s'adaptant aux goûts actuels. Est-ce que c'est la régalade ? Réponse dans ce nouvel épisode de Fin Du Game. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
De loin, Hyper Light Drifter se présentait comme un Zelda-like avec des néons sous les pixels. Dans les faits, c'est un jeu qui oscille entre des phases d'actions frénétiques et des moments de contemplation teintés d'une étrange mélancolie. Si son créateur Alex Preston n'avait auparavant aucune expérience dans le game design, il a su s'entourer et donner naissance à une œuvre aboutie et personnelle. Retour dans ce monde où tout est malade dans ce nouvel épisode de Fin Du Game. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Personne n'y croyait et pourtant, en 2016, la licence DOOM a fait un retour fracassant. Alors que le FPS moderne s'embourbait dans les scripts et les combats sous couverture, ID Software nous a rappelé qu'un shooter pouvait être frénétique et nerveux. Comment ce reboot fait-il le pont entre les origines de la saga et le jeu vidéo contemporain ? Réponse dans Fin Du Game, l'émission qui va au bout des jeux. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Après les rêves et les grands anciens, Fin Du Game revient à la réalité avec Gone Home, un drame familial et intimiste. Déguisé en "walking simulator", le titre de Fullbright est en fait un jeu enquête dans lequel nous devons explorer, fouiller une maison déserte pour reconstituer l'histoire de la famille Greenbriar. C'est un jeu avant-gardiste, autant dans son game design que son propos, abordant des sujets durs et concrets. Il nous fallait évidemment vous en parler jusqu'au bout. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Chegamos ao 10° episódio! E para celebrar essa pequena conquista , pedimos perguntas de diversos tipos a vocês ouvinte e veja só no que deu. Episódio apresentado por Brunna, @japaeamae, Samara e Silas!
Ça y est, c'est la reprise ! Et pour commencer cette nouvelle saison sur des bases saines, l'équipe de Fin Du Game a décidé de rendre justice à Bloodborne. Un jeu qui avait déja été abordé dans l'émission par le prisme des Souls, mais qui méritait bien son épisode à lui. Son univers lovecraftien, sa bestialité, sa façon de nous transformer ; malgré ses ressemblances avec les autres titres de From Software, il propose une experience unique et d'une élégance rare. Retour sur le meilleur des cauchemars. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Du sable à perte de vue. Le soleil qui trône fièrement en haut de la montagne... Et non, ce n'est pas le début du récit de nos vacances, mais bien celui de Journey, jeu iconique dont il est question dans cet épisode estival.En s'inspirant du "Monomythe", Jenovah Chen et son équipe ont tenté de façonner une œuvre universelle, minimaliste mais soignée. Et le temps semble confirmer leur réussite, puisque 7 ans après sa sortie, Journey revient régulièrement dans les débats, surtout s'il s'agit de parler d'Art dans le jeu vidéo. Pour vous, Fin Du Game enfile sa meilleure écharpe et retente le voyage. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Pour finir cette première saison de Fin Du Game, l'équipe grimpe en haut de la montagne nommée Breath Of The Wild. Jeu-surprise, jeu-phénomène, cet opus revient à l'essentiel de la saga Zelda, tout en envoyant balader certains de ses codes les plus profonds. En s'inspirant de Skyrim et de Minecraft, l'équipe de Fujibayashi a donné un nouveau sens au "monde ouvert" : un espace de jeu qui nous appelle sans cesse à l'explorer et le comprendre. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Mais que s'est-il passé à bord de l'Obra Dinn ? C'est la question que nous pose Lucas Pope dans ce jeu d’enquête maritime et fantastique. Pour y répondre, le créateur de Papers Please nous donne le pouvoir de voyager dans le temps et l'espace, à travers des scènes tragiques ultra-détaillées. Mais en retour, il exige de nous une rigueur et une attention de chaque instant, quitte à laisser sur le coté les moins investis. Est-ce le prix à payer pour jouer au détective ? Réponse dans ce 15ème épisode de Fin Du Game. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Dans ce nouvel épisode, l'équipe de Fin Du Game s'attaque à un classique : Shadow Of The Colossus. Sorti, ressorti, refait, ce jeu unique a traversé les générations et n'a jamais vraiment cessé de faire parler de lui. Pour comprendre pourquoi, revenons donc sur ses colosses majestueux, son monde silencieux et - il faut l'admettre - ses contrôle un peu boiteux. Note : aucun cheval n'a été blessé pendant cet enregistrement. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Quand Symphony Of The Night rencontre Microcosmos, ça donne Hollow Knight et donc un épisode Fin Du Game plein d'amour. Comment la Team Cherry, sans grosse expérience dans le milieu, a réussi à faire éclore un des meilleurs Metroidvanias de ces dernières années ? De la générosité, de la précision et des marmonnements, on vous dit tout (ou presque) en une grosse heure ! Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
This JCO Podcast provides observations and commentary on the JCO article “PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study” by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma. Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens. As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure. One important question has been: how best to distinguish those disparate groups? Over the years, various prognostic scoring systems have been devised. The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors. However, only 7% of patients are in both the most and least favorable groups. The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection. Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens. More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets. FDG-PET scanning has revolutionized our management of patients with lymphoma. In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score. In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected. In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma. This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle. Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy. Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy. Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy. Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death. Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores. Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown. Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors. But we are clearly doing this all wrong. Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy? Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma. High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies. Unfortunately, those tests do not provide a target against which to direct a specific agent. In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome. Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goal of treatment should be anticipatory, risk-adapted strategies whereby patients with a high likelihood of benefit may receive standard of care, unless there is another clinical question being addressed. On the other hand, those unlikely to benefit as determined prior to therapy should be spared the waste of time and toxicity and treated with novel regimens directed at specific targets. Both groups should be monitored during treatment for the emergence of mutations, with treatment altered accordingly. Yes, we may be a long way from having the appropriate tools for such an approach. But, to quote the geneticist, molecular engineer and chemist George M. Church, “The best way to predict the future is to change it”. Anticipatory, risk-adapted strategies could do just that. This concludes this JCO Podcast. Thank you for listening.
Des extra-terrestres qui se transforment en tabouret et des histoires d'amour en apesanteur : c'est le programme de ce nouvel épisode de Fin Du Game consacré à Prey. Sorti en 2017, le dernier titre du studio Arkane est un "immersive sim" ambitieux, dans sa structure comme dans son système de jeu. Arrive-t-il à tenir la distance ? Réponse en une heure. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Tous les jeux Mega Man-like ne sont pas créés égaux et dans le cas de Venture Kid, il faut avouer que le studio Snikkabo et l'éditeur FDG Entertainment ont frappé en plein dans le mille! Venture Kid assume entièrement ses racines en proposant des graphismes issus de l'ère 8-bits, rappelant ceux des premiers titres de la célèbre franchise Mega Man.Contrairement à Metagal, Venture Kid offre un aventure grandement inspirée du célèbre petit guerrier bleu sans toutefois copier presque le tout pour le tout les éléments de la franchise de Capcom.!-------------Merci à FDG Entertainment qui nous a gratuitement fourni une copie du jeu afin d'en faire la critique. L'éditeur/développeur nous autorise également à diffuser le contenu du jeu sans restrictions et n'intervient aucunement dans l'attribution de la note finale. #Article13 #SaveYourInternet--------------Pour nous suivre sur nos autres plateformes: ► Site web officiel: http://m2gaming.ca/ ► Facebook: https://www.facebook.com/m2gaming/ ► Twitter: @M2Gaming ► Twitch: https://www.twitch.tv/m2gamingcanada--------------Vous voulez soutenir la chaîne?► Quelques uns des produits que nous utilisons: https://amzn.to/2pTNLZ1► Achetez vos jeux via notre lien d'affiliation: https://amzn.to/2GmptgY
Voyages dans le temps, histoires glauques et bains nocturnes : la vie est étrange à Arcadia Bay. Dans cet épisode, l’équipe de Fin Du Game retourne en 2015 pour étudier Life Is Strange. Un jeu très (trop?) référencé qui arrive néanmoins à nous replonger dans les doutes et les espoirs de l’adolescence, par ses mécaniques temporelles et sa mise en scène cotonneuse. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Dans cet épisode, Fin Du Game va au bout de The Red Strings Club. Développé par le trio de Deconstructeam, ce jeu narratif nous fait vivre une aventure cyberpunk à travers 3 points de vue différents. Malgré des mécaniques parfois bancales, le titre arrive à aborder des thématiques comme le bonheur et la liberté avec une intelligence certaine. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
A l’occasion de la sortie de Sekiro : Shadows Die Twice, l’équipe de Fin Du Game revient sur les “Soulsborne” et tente de faire le point sur l’œuvre d’Hidetaka Miyazaki. Si la série est encore souvent résumée à sa difficulté, c’est bien son audace et sa richesse qui lui ont permis de marquer autant les esprits, jusqu’à devenir une référence pour de nombreux designers contemporains. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
What Remains Of Edith Finch, c'est le sujet de ce nouvel épisode de Fin Du Game. Le jeu de Giant Sparrow est un "walking simulator", mais pas seulement, puisqu'il nous fait revivre des scénettes tragiques grâce à des phases de jeu très différentes les unes des autres. Une histoire de mort(s) donc, mais aussi d'héritage familial et de transmission. Exserv, Maxime et Hugo revisitent avec vous la maison des Finch. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Shlomo Koyfman from the Cleveland Clinic, lead author on "Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Koyfman. It's a pleasure. So first, can you give us a general overview of what this guideline covers? Yeah, so this is an exciting guideline because it covers a topic that we don't usually think about in head and neck cancer in a formal way, and that is management of the neck in squamous cell cancer of the oral cavity and the oropharynx. So there's a lot of literature and guidelines out there on how to manage oropharynx cancer, which is becoming a more and more common cancer, especially in the HPV-positive era, less so on oral cavity. But a lot of times it's focused on people who don't get surgery, chemoradiation, or people who do get surgery and TORS, Transoral Robotic Surgery, and different approaches. But rarely do we have something focus on management of the neck per se, which is really, really important in these cancers and often overlooked in favor of the primary tumor itself. So these guidelines really take us through some salient questions in how to manage the neck in these two cancers. And what are the key recommendations of this guideline? The recommendations came off of six fundamental questions, three in oral cavity and three in oropharynx. There are some commonalities between the two and some differences. A lot of the fundamental questions revolve around surgical quality, and neck dissection is the standard surgical approach for management of the neck in these patients. And as we enter the quality era, how do we define benchmarks of surgical quality, which is one thing that it deals with. The other is when to do adjuvant therapy like adjuvant radiation or chemoradiation. We also deal with when to do surgery for the neck or to do nonoperative approaches like radiation or chemoradiation. And then lastly, how do you follow patients after you've treated them? So those are kind of the salient issues that we dealt with. And what we came out with was nothing earth shatteringly new, but I think the way it was organized and systematically put together, I think it's going to be really, really helpful for people. So some of the most important findings that this recommendation does, I think this is the first that incorporates surgical quality, as I mentioned before. So specifically neck dissection should have 18 or more nodes as multiple studies have shown that that's associated with better outcomes. And similarly we define for different diseases of oral cavity and oropharynx, and depending on what kind of tumor it is and where, what nodal levels should be dissected or treated, whether surgically or nonsurgically, and when to do just one side of the neck versus both sides of the neck. So I think there's a lot of good guidance there in terms of the surgical quality. From a standpoint of adjuvant therapy, we define pretty clearly indications for when after surgery for oral cavity cancer, for example, when radiation should be added and when chemoradiation should be added, and I think that's very helpful. And especially for the neck itself, there's been confusion about what happens if I have 30 nodes taken out and they're all negative but I have a big, large primary tumor. What do I do with the neck? Do I radiate it? Do I not radiate it at one side, both sides? And this guideline gives some pretty clear guidance in different scenarios about how to think about that, which is pretty novel and really important, I think. I get questions about this all the time. It comes up in tumor boards all the time, and it's pretty practical. And mostly what we say is if you have a primary tumor that's like a T3 or T4 oral cavity cancer or it approaches midline, either a contralateral neck dissection should be done or radiation should be done to the contralateral neck. And even if you have a lot of lymph nodes taken out and they're negative, if you have very high-risk primary tumor features like very large tumor or multifocal perineural invasion, those kinds of things, even with a negative neck dissection we still typically do treat the neck. So the next recommendation that's really helpful is who can be observed after surgery? And specifically low-volume N1 you can consider observing in oral cavity cancer, whereas N2 or N3 patients all need radiation or chemoradiation in the setting of extranodal extension and positive margins. We did come out pretty firmly advocating for bolus cisplatin 100 milligrams per meter squared every three weeks as recent studies suggest that weekly cisplatin or other regimens are not as effective, and we were pretty clear about that. We were pretty synchronized with recent ASCO-endorsed guidelines in oropharynx cancer that say similar things. In addition, one of the very important questions that comes up is a surgeon will say, well, I'm cutting out the neck tumor, and I know it comes to midline and he's got a bunch of nodes on the right side, but do I really need to do a left neck dissection? Aren't you going to radiate it anyway? And that comes up all the time. Is radiation adequate to manage a clinically negative neck in oral cavity cancer and oropharynx cancer? I think in oropharynx cancer everybody feels pretty comfortably yes. I think in oral cavity cancer it's been somewhat controversial. We favor neck dissections when possible, but if radiation is known to be happening, especially to an elective contralateral neck, that that is adequate therapy. However, we're pretty strong in the fact that neck dissections are the tried and true way to treat oral cavity cancer and that in a T2 or above tumor where a neck dissection is indicated, just resecting the primary and leaving the neck to elective radiation is not something that we thought there was enough evidence for to advocate, and we still advocate classic neck dissection first followed by adjuvant radiotherapy as indicated. One area of controversy that we did touch on is the issue of early stage tongue cancers and whether they need a neck dissection at all. And we came down pretty consistently with all of the co-authors on the guideline that we advocated for a neck dissection for all patients with oral cavity cancer unless it is a very small tumor that we define with very compliant patient who is amenable to very rigorous follow-up that has been done in Europe and in some other places with, specifically, people trained in careful neck ultrasound techniques. So all of those really help guide, both in early stage and more advanced stage, how to manage the neck and oral cavity cancer. And in oropharynx cancer, again, many of the same quality metrics apply. We have some guidance about when doing transoral robotic surgery how to reduce bleeding risk by ligating feeding blood vessels, which is an important addition. We also discuss the fact that, as opposed to lateralized oral cavity patients where a unilateral either neck dissection of radiation is often indicated, in oropharynx cancer the group felt very strongly that bilateral neck should be treated. And typically if tumors extend to midline or involve the posterior oropharyngeal wall, which has bilateral drainage, that either bilateral neck dissection should be performed in those cases or a unilateral neck dissection can be done as long as adjuvant radiation is planned to both necks. Finally, a couple of very important questions of who should not be treated surgically and who should be treated with a nonoperative chemoradiation based approach. In oral cavity cancer, as long as they were not metastatic, we felt people should be resected as long as they were surgically resectable and medically operable. In oropharynx cancer, however, anybody who had unequivocal extranodal extension of nodes into soft tissues or involvement to the carotid artery or extensive cranial-nerve involvement or skull-based involvement by extensive nodal disease are not good candidates for surgery and should be preferentially treated with chemoradiation. That was pretty strong. And finally, the other thing we gave clarity on is when we treat oropharynx cancer with chemoradiation, how do we follow them and when do we decide to do a neck dissection or not? And essentially we recommended a PET CT scan at 12 weeks. And as long as that was negative, a neck dissection should not be done. If you don't have a PET scan and you just have high quality CT or MRI but all of the neck disease has resolved, similarly there should be no neck dissection. And then most importantly, the situation we all face which is very complex is what happens when you have a PET CT done three to four months after treatment and you have small nodes that are still there? You have a little bit of uptake. The FDG avidity is much less than it was. There still is a lesion there, but it's much better and the patient is feeling well. And we felt pretty comfortable not doing a standard neck dissection on those patients but rather following them closely with a follow-up CT scan two to three months later and continual assessment and reserving surgery for obvious progressive disease. So why is this guideline so important, and how will it change practice? So this guideline is really important because head and neck cancer being not the most common cancer, and especially because head and neck cancer is not really one disease-- there's so many different diseases. Even oral cavity and oropharynx, there's quite a bit of variability in how we think about it. There's not a one size fits all recipe for how to manage people properly, and that leads to a lot of confusion and sometimes doubt as to what the best thing to do is in these patients. And that is a very common thing. So I think the most important reason why these guidelines are helpful is they're really clear. They give really clear guidelines of if you're going to do surgery, here's the expectations of what nodal levels to take out and how many nodes to take out. Here's when you should do adjuvant radiation. Here's when you should do adjuvant chemoradiation. Here's when you should treat one side of the neck. Here's when you should treat both sides of the neck. If you're not going to do surgery, here's when you do radiation. And for oropharynx cancer, here's when you can consider surgery. Here's where surgery is not the best idea. And when you treat them and if you do surgically, here's how you do it. If you do with radiation, here are the nodes that should be treated, the nodal levels. And finally, after you do that, how do you watch and act to make sure that people don't fail? So I feel like all of those things lend a lot of clarity to some complicated decision-making processes for these patients, and this really lends clarity to that, which should help kind of lend consistency of practice. That's really our goal. Our goal was there a lot of great docs taking care of these patients out there, but patients are treated in very different ways depending on who they're seeing and where you go. Our goal was to try to increase the consistency of how people are treated no matter where they are. And if practitioners, surgeons, radiation oncologists, medical oncologists see this guideline and kind of follow it and, of course, reach out with any questions at any time, then what we'll be able to do is kind of harmonize the way patients are treated in this country, which should help, I think, the quality of care. And finally, how will these guideline recommendations affect patients? They're going to affect patients because right now a lot of patients get great care, but there are some patients that are not getting ideal care either because maybe they're in parts of the country that don't have the same access to resources or they're in places where the volume of these kind of very complicated and yet not so common diseases aren't seen as high and there's confusion about how to manage them or what the quality metrics are. I think patients are going to be affected knowing, hey, if I'm going to have a neck dissection, here's what I should be asking to make sure my surgeon knows to do and does consistently to make sure it's of high quality. Here's where I think I should be treated with surgery, maybe I shouldn't be treated with surgery, and here's how to follow me. Because there is a lot of variability in how patients are treated, and sometimes there's too many surgeries being done, not enough surgeries being done. If they're being done, maybe they're not the best quality. Even if we don't treat with surgery and we do chemoradiation, we're watching them and we may not be following them as closely, and then people may be recurring and we're not picking it up closely enough. So I think it's going to harmonize, for patients, the way they're ultimately treated. If everybody in the country is treated relatively compatible with this guideline, I think the standard of care will go up across the board. Great. Thank you so much for your work on this important guideline, and thank you for your time today, Dr. Koyfman. Thank you so much. And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.
Dans cet épisode, l'équipe de Fin Du Game revient sur Her Story et sa façon de raconter son histoire morcelée. En jouant avec les codes du polar psychologique et un moteur de recherche approximatif, son créateur Sam Barlow a cherché à stimuler notre imagination et notre sens de la déduction... Quitte à nous laisser sans réponse. Est-ce que ça fonctionne ? Réponse en moins d'une heure. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Pour ce cinquième épisode, replongeons ensemble dans INSIDE, le second jeu de Playdead, studio danois mené par Arnt Jensen.A l'instar de son ainé LIMBO, c'est un jeu qui ne dit pas un mot, et nous faire vivre le voyage d'un jeune garçon fragile au royaume de la déprime. Mais cette fois-ci, il y a beaucoup plus à voir, à entendre et à comprendre. On revient donc sur les grands moments qui ont fait ce jeu unique, son atmosphère singulière et sa réflexion sur le contrôle. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Pour fêter le début de l'année 2019, ce quatrième épisode de Fin Du Game se penche sur The Last of Us, considéré depuis sa sortie en 2013 comme un classique. Présent aux côtés de Sony et de la PlayStation depuis le tout début, le studio Naughty Dog passe du grand spectacle d'Uncharted à une aventure plus intimiste, oppressante et touchante dirigée par Neil Druckmann. Véritable tournant pour le studio, The Last of Us marque également le début d'une nouvelle ère pour les jeux triple A. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Ce troisième numéro de l'émission Fin Du Game, présentée par ExServ, Hugo et Maxime revient sur Firewatch, le tout premier jeu du studio Campo Santo. Constitué de vétérans de l'industrie, il mélange les règles du metroidvania à une narration intensive, dans un jeu qui favorise l'imaginaire et nous parle de fuite et de regrets. En plus de revenir sur les intentions du studio, nous nous penchons sur la structure du jeu et son utilisation de la narration pour compenser l'absence de tout danger ou combat. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtA- Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Pour ce "deuxième pilote" de l'émission Fin Du Game, ExServ, Hugo et Maxime s'intéressent cette fois-ci à God of War, célébré comme étant le jeu de l'année par The Games Awards devant d'autres poids lourd comme Read Dead Redemption 2. Redémarrage complet de la série, le dieu de la guerre revient avec une proposition très différente et se retrouve dans le rôle improbable de père. Sur plus d'une heure, on se penche sur les intentions de l'homme derrière le jeu, Cory Barlog, sa vision pour un titre tiraillé entre ses envies de raconter une histoire et de rester un jeu vidéo à grand spectacle. Pour soutenir Fin Du Game : https://www.patreon.com/findugame - Pour rejoindre le club de lecture FDG : https://discord.gg/SFxKYt - Merci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
On October 19th, 2018, Rami Doukky spoke with Drs. Flores, Flaherty and Bokhari about their recently published article entitled ‘The prognostic value of quantitating and localizing F-18 FDG uptake in cardiac sarcoidosis’. The authors of this article have provided a PowerPoint file which summarises the contents of the paper and is free for re-use at meetings and presentations: http://bit.ly/2PBdvJc The article is available at: https://rdcu.be/bbBY5 Be sure to subscribe on your mobile device - search 'JNC/ASNC Podcast'.
Dans cet épisode pilote de l'émission Fin Du Game, ExServ, Hugo et Maxime reviennent sur Celeste : le seul jeu vidéo indépendant nominé aux Games Awards dans la catégorie Game of the Year. Aux côtés de God of War, Red Dead Redemption 2 ou encore Monster Hunter World, le jeu de plateforme développé par MattMakesGames fait figure d'outsider. En moins d'une heure, on tente d'expliquer pourquoi il s'agit d'un jeu vidéo essentiel en revenant notamment sur sa narration portée par le gameplay et sa bienveillance à toute épreuve. Pour soutenir Fin Du Game : https://www.patreon.com/findugamePour rejoindre le club de lecture FDG : https://discord.gg/SFxKYtAMerci à notre sponsor Third Editions, maison d'édition spécialisée dans les ouvrages sur les jeux vidéo : https://www.thirdeditions.com
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. FDG-PET CT was recently introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, can we improve on its diagnostic performance? Well, to learn more you have to listen to the upcoming featured discussion, right after these summaries. Our first original paper this week describes a potential novel therapy for hypertension. In this study from first author Dr Hu, corresponding author Dr Soong, from Yong Loo Lin School of Medicine National University of Singapore, authors showed that galectin-1 is a key regulator for proteasomal degradation of CaV 1.2 channels. L-type CaV 1.2 channels are known to play crucial roles in the regulation of blood pressure. In a series of elegant in vitro and in vivo experiments, the authors showed that galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and thereby, exposing specific glycines for polyubiquitination. This mechanistic understanding provided the basis for targeting CaV 1.2 galectin-1 interaction and demonstrated the modulatory role that galectin plays in regulating blood pressure. The study, therefore, offers a potential novel approach for the therapeutic management of hypertension. Direct oral anticoagulants or DOACs, are surpassing warfarin as the anticoagulant of choice for stroke prevention in non-valvular atrial fibrillation. However, DOACs outcomes in elective peri-procedural settings have not been well elucidated and remain a source of concern for clinicians. The next paper in today's issue was a meta-analysis designed to evaluate the peri-procedural safety and ethicacy of DOACs versus warfarin. For author Dr Nazha, corresponding author Dr Spyropoulos, from the Feinstein Institute for Medical Research in Northwell Health at Lenox Hill Hospital in New York, reviewed the literature for data from phase three randomized controlled trials comparing DOACs with warfarin in the peri-procedural period among patients with non-valvular atrial fibrillation. Sub study from four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF. The short-term safety and ethicacy of DOACs and warfarin were not different in patients with non-valvular atrial fibrillation peri-procedurally. Under an uninterrupted anticoagulation strategy, DOACs were associated with a 38% lower risk of major bleeds compared to warfarin. The next paper presents results from the Sarcomeric Human Cardiomyopathy Registry or SHARE, which combined longitudinal data sets curated by eight international hypertrophic cardiomyopathy specialty centers to provide a better understanding of the factors that contribute to heterogeneous outcomes in lifetime disease burden in patients with hypertrophic cardiomyopathy. First and corresponding author Dr Ho from Brigham and Women's Hospital and colleagues analyzed longitudinal clinical information on 4,591 patients with hypertrophic cardiomyopathy. By examining the data set spanning more than 24,000 patient-years, the mortality of patients with hypertrophic cardiomyopathy was shown to be 3-fold higher than the general population at similar ages. The lifetime cumulative morbidity of hypertrophic cardiomyopathy was considerable, particularly for patients diagnosed before age 40 years and patients with sarcomere mutations. Atrial fibrillation and heart failure were the dominant components of disease burden. Thus, young age of diagnosis and the presence of sarcomere mutations are powerful predictors of adverse outcomes in hypertrophic cardiomyopathy. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies. The final original paper this week provides molecular insights into atherosclerosis and it shows that defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Now, we know that atherosclerotic blocks demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine lesions. In today's paper, first author Dr Shah, corresponding author Dr Bennett from University of Cambridge and colleagues studied levels of 8-oxoguanine and its regulatory enzymes in human atherosclerosis. They found that human plaque vascular smooth muscle cells showed defective nuclear 8-oxoguanine repair, associated with reduced acetylation of the base excision repair enzyme 8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base excision repair defect in vascular smooth muscle cells alone markedly reduced plaque formation, thus indicating that endogenous levels of oxidative DNA damage in vascular smooth muscle cells promoted plaque development. And that brings us to the end of this week's summaries. Now for our feature discussion. Prosthetic valve endocarditis is a life-threatening complication. However, making a timely diagnosis of prosthetic valve endocarditis before the occurrence of severe complications is really difficult. Now, FDG-PET CT has recently been introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, previous studies reported only modest diagnostic accuracy and may have been hampered by confounders. But today's study, our feature study in Circulation, addresses this issue. We have none other than the corresponding author, Dr Ricardo Budde from Erasmus Medical Center in Rotterdam, the Netherlands, and our dear associate editor, Dr Victoria Delgado, who is in Leiden University Medical Center, also in the Netherlands. So please tell us, how does your study help us address this issue of the accuracy of FDG-PET CT Dr Ricardo Budde: What we actually did is that of course endocarditis is a relatively rare disease, so we had six hospitals in the Netherlands that collaborated on this study and in each of the hospitals we searched for PET CT scans that were performed in patients with a prosthetic heart valve, either because they were suspected of having endocarditis, or if they were meant for other purposes, for example oncological follow-up. Then we grouped all those CT scans together, interpreted the PET CTs anew by dedicated interpreters, and then compared the findings with the actual diagnosis in the patient, which of course is always difficult in endocarditis because to make the diagnosis is difficult. So, also, one year follow-up period was included in that to be absolutely certain whether the patient had endocarditis or not. By taking this whole cohort of patients, we were able to determine the diagnostic accuracy of PET CT, as well as by using a logistics model, identify confounders which influence the diagnostic accuracy of PET CT. I think the study that we did addresses several important aspects and the way it helps physicians in actually interpreting and implementing PET CT to diagnose endocarditis is two-fold. First of all, we identified confounders that have to be taken into account when interpreting and using the PET CT. For instance, low inflammatory activity at the time of imaging and the use of surgical adhesive during a prosthetic heart valve implantation are confounders which should be taken into account when interpreting the PET CT. Furthermore, the guidelines have always insisted on not to use or use it very cautiously PET CT within the first three months after prosthetic heart valve implantation. However, we showed that actually this period after implantation does not necessarily have to be taken into account as also a good diagnostic accuracy can be obtained within the first three months after implantation. Dr Carolyn Lam: Ricardo, that's wonderfully put. I don't do a CT, PET CT, routinely. In fact, I am echocardiologist and it used to be that infective endocarditis was diagnosed with echo. So Victoria, tell us, how does echo stand now with this information? Dr Victoria Delgado: That's a very good question but I think the guidelines set a very clear figure of how the diagnostic workup of patients with prosthetic valve endocarditis should be performed. An echocardiography is the first imaging technique. The point is that transthoracic echocardiography in patients with suspicion of prosthetic valve endocarditis is very challenging. In terms of ideal, echocardiography is probably the best imaging technique to do first to evaluate whether it is endocarditis or not. It's difficult, we have to take into account that for a specific prosthetic valve, particularly mechanical, the shadowing can make that we don't see the [inaudible 00:10:22] and sometimes it's difficult, particularly in the early phase immediately after implantation, all the inflammation can be confounder for presence of endocarditis. In those cases, I think that this study provides additional and important data highlighting which are the confounders when you use PET CT to evaluate depressions of endocarditis. I think that, when you take into account those confounders, the accuracy of this technique is very good in order to make or help in the diagnosis of these patients. So, echocardiography, I think that will remain as our first imaging technique to rule out [inaudible 00:11:10] we can see but in those cases where the diagnosis is not confirm or rule out with transthoracic and transesophageal echocardiography this study provides additional data and important data showing that PET CT is a valuable complementary imaging diagnostic test for these patients. Dr Carolyn Lam: Ricardo, would you agree with that because I think your study also emphasized that perhaps FDG-PET CT should be implemented early in the diagnostic workup to prevent the negative confounding effect of the low inflammatory activity? So how do we put this all together? Dr Ricardo Budde: Well actually, I agree with Dr Delgado that echocardiography is and should be the first-line test that you do if you have a patient that has a suspicion of endocarditis. I mean, the advantages of echocardiography are many and it's non-invasive, it's bedside-available if needed, it's patient-friendly, and it provides a huge amount of information so you should always start with echocardiography. However, sometimes it can be difficult by echocardiography, for the reasons just explained by Dr Delgado, and I think then PET CT should be considered. And when you want to do a PET CT, then you should do it early within the diagnostic workup. Actually, in the article, one of the figures is a flow chart which we provide, and it provides information on how we think PET CT can best be implemented in the workup of endocarditis. In this flow chart we also start with doing an echocardiography and also, importantly, consult the endocarditis time to make initial classification of whether it's a rejected, possible, or definite prosthetic heart valve endocarditis. After that, you can follow the flow chart and see when you can best implement PET CT, in our opinion. Dr Carolyn Lam: Indeed Ricardo, I am so glad you brought up this figure and listeners, you have to take a look at it. I can imagine that everybody will be using this and discussing it and how to incorporate this in the workflow. And indeed you do start with either transthoracic or transesophageal echo and blood cultures, so thank you for clarifying that. Now, for our clinicians out there, are there any situations you may be telling us to be a little more careful? Could you put it simply for us when it comes to the FDG-PET? Dr Ricardo Budde: You mean when not to perform a PET CT? Dr Carolyn Lam: Yeah, or when we have to be really careful about inaccuracies. Dr Ricardo Budde: I think, of course, the confounders that we indicate in the article, especially if bioglue has been used by the surgeon during the initial surgery. We know that bioglue can be seen on a PET CT as a false positive uptake of FDG and it's also important to note that this is a phenomenon that can persist for a very long time after a valve implantation. It could be for years, so especially that I think is a very important confounder to take into account and be careful when you interpret PET CT or use the PET CT and always read the original surgical report if it is available to obtain this information. Dr Carolyn Lam: That's wonderful advice. Victoria, do you have anything to add? Dr Victoria Delgado: No, I think that Dr Budde explained perfectly this figure that is key in the article and also how to evaluate patients with suspected endocarditis of prosthetic valve. One thing that sometimes we forget is starting from the first step that is a good clinical history which includes also a good evaluation of previous history and, if possible, what has been done in the patient. I think that this key information to understand the findings on the echocardiography, transthoracic or transesophageal, and the subsequent investigations that you are going to perform. Either CT which is considered, for example, when you have a definitive prosthetic valve endocarditis and you want to rule out potential complications such as abscess, for example, and if you perform a PET CT or other imaging modalities that then also indicate the presence of infection like, for example, [inaudible 00:15:26] leukocytes with PET, for example. Dr Carolyn Lam: And I just want to end up with one little point. Ricardo, how about the fact that part of your results don't corroborate the ESC guideline recommendations that they say you have to avoid FDG-PET in the recently implanted prosthetic valve. How do you feel it's going to play out for clinicians? Dr Ricardo Budde: Well, I think the 2015 ESC guidelines on endocarditis are a very important document. One must take into account that the inclusion of PET CT in the ESC guidelines was a major step, and some might say that it was a little premature to include the use of PET CT because the number of data that was out there were still relatively limited. I think it's something that we are learning along the way. Now that we are using PET CT more often we are more aware of what we do to findings that we get and also the findings that we have within specific timeframes after the implantation of a prosthetic heart valve. One of the things that I think is desperately needed also at the moment is to have a prospective study where we would do PET CT in patients after implantation of a prosthetic heart valve that do not show any signs of endocarditis where we do PET CT just to determine these normal uptake values. I think that would be a major contribution to the whole learning experience that we're currently having with implementing PET CT within prosthetic heart valve endocarditis. Dr Carolyn Lam: Indeed, and Ricardo your paper has added significantly to our understanding. Readers, remember, it's Figure 6 of our feature paper this week. It is a beautiful figure. Pick it up, take a look. In the meantime just thank you so much Ricardo and Victoria for joining me today. Listeners, don't forget to tune in again next week.
PET-CT scans provide detailed information on where cancer is located, whether it’s spreading and if treatments are working. Dr. Carlos Garcia explains how this test works, what to expect if you’re having one and how your doctor uses the results. TRANSCRIPT Intro: MedStar Washington Hospital Center presents Medical Intel where our healthcare team shares health and wellness insights and gives you the inside story on advances in medicine. Host: Thanks for joining us today. We’re talking to Dr. Carlos Garcia, Medical Director of Nuclear Medicine at MedStar Washington Hospital Center. Today, we’re talking about the benefits of PET CT scanner. Dr. Garcia, what is a PET CT scanner and when is it used? Dr. Garcia: So, a PET CT scanner is kind of a gold standard for cancer imaging. Just like in the past it was called a CAT scan, now they’re called CT scans, are for anatomic imaging of multiple causes, whether they’re cancer or not. PET CT is 99.9 percent dedicated to cancer imaging. The difference between a PET scanner and a CT scanner is that a PET scanner will rely on the cells being alive and consuming a specific type of substance that makes them show up on the scan. This substance is normally either produced or it circulates in your body. And we add radiation to it and that’s why we can see it on the images. So, it’s a combination now of anatomic imaging from the CT portion of the exam and functional or metabolic imaging from the PET portion of the exam. PET stands for positron emission tomography. Positrons are just basically an energy source that will, you know, produce an amount of radiation that we can translate into images, and the more active a cell is--especially the cancer cells tend to be more active than normal cells--the more they’re going to emit this type of energy, the more they’re going to take up this type of radioactive substance that they would normally not, and that’s how they show up in a more avid, or they light up on the scan, if you will. Host: So, how is the substance introduced to this other substance that you mentioned in order for it to show up on the PET scan? Dr. Garcia: So, what we do is we make the patient the source of the radiation. We inject the patient with a modified version of glucose, which is the most common one; that’s why I am going to use that as an example. It’s called fludeoxyglucose, or FDG for short. You’ll see that many of our exams have acronyms for that same reason. It’s kind of a hard, long word. So, we inject the patient with this glucose substance, and all the cells in the body normally will use glucose as energy. Cells that replicate faster or grow out of control, as cancer cells do, will use more glucose because they require more energy to sustain this growth pattern. So, the cells that take up more glucose will take up more of the radioactive glucose that we have injected into the patient, and that’s why they will shine in comparison to the background of normal cells. These cells will look bigger, darker and brighter because they just take up more of the radioactive substance that we tricked the body into taking because it doesn’t know it’s radioactive; it just thinks it’s glucose. Host: So, what are the advantages of combining a PET scan with a CT scan for cancer? Dr. Garcia: For many, many years, when we did not have PET images available, we only used CT imaging, which could provide us only with an anatomic version of whatever is going on inside the body. The problem with this is sometimes you can see a tumor—we’ll just use that as an example, and only the inner portion of the tumor might be where all the cancer is, and the rest of it might be just inflammation resulting from the presence of that cancer or tumor. The PET scan can differentiate that sometimes. It can show you what is the actual size of the live tumor inside of a structure that might be, let’s say for example, 5 cm larger, but it’s not all tumor. This helps in many ways to guide the therapy. One of the main applications of knowing this difference between what is functional or what is metabolically alive versus just the anatomy, is that when you apply this to radiation purposes for treatment, for example, the radiation field that will be attached, I’m sorry, that will be used for that particular tumor will only be the size of the part of the tumor, or the part of the mass, that is actually alive, so you can actually make it a little more circumscribed and more directed. So that’s one of the applications when you talk about it. Now it’s called all hybrid imaging--that is the gold standard nowadays of all cancer or oncologic imaging. And now the new hybrid imaging scanners like the ones that we have here, will overlap these images, and they’re called fused activity, and you can definitely see the background and over the background of anatomy overlap with the cells that are actively replicating that turn out to be cancer cells. Host: So, having the fused images really provides a deeper layer and a deeper perspective for both the imaging team and the physician. Does the patient also get the chance to see those images? Dr. Garcia: When we have the opportunity to show the images to the patients, by all means. Nine out of 10 times, the physicians that have ordered the tests are comfortable with the patients knowing the results. We always want to extend the courtesy of the referring physician to be directly involved with the patient and them communicate the results, but we have had scenarios in which the patients are very comfortable knowing and they are very, very well versed in their own disease process, as it should be nowadays, and we are happy to show them the images. The overlapping of the anatomic portion of it and the live cell, the metabolic portion of it, it completely takes away from having to even point at the screen. Everything becomes very, very obvious and you can use different color schemes to bring out certain cell types, so it makes a picture worth a million words instead of a thousand words. And all the physicians within the hospital, they have the opportunity to be able to see these images on Enterprise-wide imaging viewer that they have access to as well. So, that makes our job very easy. Even though they’re always welcome to come to the reading room and have us show them the images directly, we can have phone conversations, them looking at the exact same images that we are looking at, and we can tell them slice number and position, and target everything they need to know. Host: Are there certain cancer types for which PET CT scan is most applicable or certain body parts that are easier to do? Dr. Garcia: That’s an excellent question because, for a long time, PET CT imaging was considered to be the, you know, savior for all types of cancer, and that unfortunately is not true. It has limitations and then it has indications that make it much more favorable. So, off the top of my head, I can tell you the top three indications that we use it here at the hospital are for breast cancer, lung cancer and lymphoma. So, these tend to be tumors that are very metabolically active. When I say metabolically active, it means that they have a tendency to take up more glucose than normal cells would, than other types of cancer would, so as long as they take up this increased amount of glucose, they will be brighter on the images and they will really stand out from the background, making the ability to detect them much, much easier. Host: It really makes the cancer sound like a living thing and like a living disease, if you will, as opposed to just this abstract. Dr. Garcia: I’m going to actually start using that way of explaining it because that actually sounds exactly right. That is, it’s a live being that has a mind of its own sometimes, and our job is to be able to detect it early, be able to apply what we see to a treatment program, and then, after the treatment program, be able to monitor the response to the therapy by seeing whether that activity that translates into a lot of glucose uptake, seeing if it went down, meaning the number of cells is going down based on the therapy. If you have less amount of cells, it’ll be less glucose that will be taken up and the shine on the exam, if you will, will decrease over time. So, we measure, we have units to measure the intensity of this activity and we use them very specifically, you know, to monitor the response to therapy because those units should go down as the number of cells within the cancer start dying as a result of the therapy. Host: If my doctor tells me that I would need a PET CT scan, what should I expect from that appointment? What will that process look like? Dr. Garcia: So, the first thing that you’re going to do is you’ll be contacted by one of our staff members from the PET CT Center, and they’re going to ask you to prepare your body to be able to absorb the glucose better, and that’s going to require for you to be fasting for at least six hours prior to the examination. So, the first glucose that you will receive, meaning the first source of energy that your body that has now been without food or drink for six hours, it will be starving. So, you prepare the body to eat something, and then the first thing that it sees is the glucose. And like I said before, it doesn’t know that it’s radioactive. It just thinks it’s glucose, so it’ll latch onto it immediately, and that way you won’t have any competition with glucose from your diet, I mean, which are carbs basically from your diet, competing for a space to latch onto certain cells. So, everything that you will have will be radioactive glucose it’ll latch on. And you arrive to the center. We give you the injection. It’s going to an intravenous injection in your arm. You’ll sit in a quiet room for anywhere between 40 or 60 minutes, and the reason why you want the quiet room is because you don’t want any stimulus to any organ in your body, so we’ll get you in a nice warm-temperature room, you’ll relax, and then about after 60 minutes from that, we will place you in the PET CT camera, and with the new cameras, the amount of time that you will spend under the camera is a lot less, so you’re looking at anywhere between a 20 to 30-minute scan from the level of your eyes down to your mid thighs. And once you conclude that portion of the exam, then the images get sent over to the radiology reading room, to the nuclear medicine reading room, for interpretation. Host: How does that doctor then use the imaging to suggest treatment for me? Dr. Garcia: So, we use a staging system, and I’m going to just use cancer, you know, as an example, which is the majority of the reasons why you do a PET CT scan. There’s a staging system to know how far or how advanced, your cancer is. And depending on how advanced your cancer is, the treatment modalities will change. Let’s use, for example, if we have a patient with lung cancer and they have a small lesion in a very circumscribed area and nothing anywhere else because the PET scan did not show that there was spread to any other organ in the body, then, in these particular cases, one of the treatment modalities might be surgery, for example. You know, I’m not a surgeon, but this is, you know like, this is, you know, one of the treatment modalities, one of the treatment options would be surgery. If, for example, the same patient has that same spot in the lung, but also has spots in his liver, also has spots in his bones, surgery may no longer be an option and a more systemic approach is necessary, meaning something, a form of therapy that will apply to your entire body since there has been spread. So, it can guide the clinician to knowing what the treatment options are for the patient, and that opens the discussion, you know, with the patient that these are now your options and this is your staging, you know, this is what we consider it to be. Because nowadays patients will do a lot of research on their own, and they come in asking you, you know, like, what is my stage? Am I stage I or stage II? What are my options based on these stages? So, that’s really, really what helps to kind of tell the patient where they are and what their options are. Host: So, really mapping the progress of that tumor through the body and then the patient’s progress, thereafter, is mapped by the images. Dr. Garcia: Correct. Mapping is a good word to use specifically for this because you will do a PET scan in various clinical phases. One of them is going to be for initial diagnosis. If a patient comes in and has an x-ray and they see a small spot on his lung, that could qualify him for having a PET scan, and they’ll isolate a nodule. Then, after that, they will apply whatever treatment option is available to the patient based on the images, and then you will have another PET scan after the therapy has been installed to monitor treatment response. So, there’s an initial treatment strategy and then a subsequent treatment strategy. That’s how PET scan is divided nowadays. So, it’s early, it’s a very important early on in the initial staging and diagnosis, and also in the monitoring treatment response phase to see if it all cleared up, if it’s spread more, or if it’s actually regressed completely. And we see patients that sometimes showed up in their doctor’s office with a small tickle in their throat. And it turned out, then they went over to their ear, nose and throat doctor, and they saw a little growth--you know, a little something, a little bulging inside their throat. And when they ordered a PET scan for this, it turned out that it was not just in that little spot, but it was in many other areas within their neck or within their chest. And, like I said, you know, once you know that, it’ll change the treatment options, but I can say definitely, this is something that I share with my colleagues, is that you sometimes, you know, you get, your day brightens up, when you compare it to a study before that showed a tremendous amount of disease, and after chemotherapy or radiation, it’s all gone. So, it’s always nice to have that dramatic effect when you see live cancer cells everywhere and all these cells are dormant--you know, they disappeared basically. We call them night and day scans. Host: For many imaging tests, patients have asked questions about or have been concerned about the level of radiation to which they’re exposed. How does the PET CT radiation dose compare to MRI or another imaging? Dr. Garcia: That’s an excellent question because that is the one thing that people will worry about a lot is radiation exposure. Yes, PET scanning alone will produce much higher radiation exposure than a chest X-ray, but you have to think about the amount of information that comes as a result of that, you know, slightly over, you know, the normal degree of exposure. People sometimes don’t understand that you just by standing around, you know, are getting a little bit of radiation from nature. And living in Denver for a year, you actually get more radiation than by having a PET scan. So, it all depends, you know, like on what kind of information you get out of it. When you do CT imaging of certain parts of your body, depending on what part of your body you’re going to image, that part of your body gets an amount of radiation. PET scanning is the injected dose that will distribute throughout your body, so the dose that you receive will be spread out through your entire body, and that is, in essence, less of a dose to each organ in your body than if you only imaged one particular area at a time. So, it is a little bit more than CT alone if you only did CT imaging, but again the risk, benefit, and the amount of information you get for only a small amount of extra radiation, which is very, very below what the maximum amount of radiation you can receive in a year is, you know, is a wealth of knowledge. Host: Are there any patients for whom PET CT scan just is not an option because of either the radiation dose or another complication? Dr. Garcia: Actually, I can’t think off the top of my head of a case in which you could not use a PET scan. We more, we more will see it in cancers that either don’t take up glucose, radioactive glucose, so it’s not the appropriate test for that particular type of cancer. Other limitations, of course, are that it has been proven through many, many studies that it is not the best examination for that particular type of cancer. There are some types of diseases that we wish we could use them on there, for those, but it’s not approved to be used for those cases. Host: Thank you so much for joining us today. Dr. Garcia: Oh, it’s my pleasure. Thank you for having me. Conclusion: Thanks for listening to Medical Intel with MedStar Washington Hospital Center. Find more podcasts from our healthcare team by visiting medstarwashington.org/podcast or subscribing in iTunes or iHeartRadio.
Dr. Paul Wang: Welcome to the monthly podcast On the Beat for Circulation Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor-in-chief, with some of the key highlights for this month's issue. We'll also hear from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field. In our first article, Barry Maron associates report on the long term clinical course of hypertrophic cardiomyopathy patients following ICD therapy for ventricular arrhythmias. They studied a cohort of 486 high-risk hypertrophic cardiomyopathy patients with ICDs from eight international centers. Of these 486 patients over 6.4 years, 94 patients or 19% experienced appropriate ICD interventions, terminating VT or VF. Of the 94 patients receiving appropriate ICD therapy, 87 were asymptomatic or only mildly symptomatic at the time of appropriate ICD interventions. Of these 87 patients, 74 or 85% remained in classes one or two without significant change in clinical status of the subsequent 5.9 years up to 22 years. Among the 94 patients, there was one sudden death in three patients who died from non arrhythmic hypertrophic cardiomyopathy related processes. Post ICD intervention, freedom from hypertrophic cardiomyopathy, mortality was 100% at one year, 97% at five years, and 92% at 10 years, distinctly lower than the risk of ischemic or non ischemic cardiomyopathy in ICD trials. Hypertrophic cardiomyopathy patients with ICDs interventions reported the heightened anxiety and expectation of future shocks. However, they did not affect general psychological well-being or quality of life. The authors concluded that in hypertrophic cardiomyopathy, unlike ischemic heart disease, prevention of sudden death with ICD therapies unassociated with a significant increase in cardiovascular morbidity and mortality, nor transformation into heart failure deterioration, ICD therapy does not substantially impair overall psychological and physical well-being. In our next article, Abdulla Damluji and associates examined the cost of hospitalizations for cardiac arrest using the US nationwide inpatient sample from 2003 to 2012. Using the log transformation of inflation adjusted costs the authors examined 1,387,396 patients who were hospitalized after cardiac arrest. They had a mean age of 66 years. Inpatient procedures included coronary angiography in 15%, PCI in 7%, intra-aortic balloon pump in 4.4%, therapeutic hypothermia in 1.1%, and mechanical circulatory support in 0.1% of patients. Notably the rates of therapeutic hypothermia increased from 0 in 2003 to 2.7 in 2012, p less than 0.001. Both hospital charges inflation adjusted costs linear increased over time. In a multi-variant analysis predictors of inflation adjusted costs included large hospitals size, urban teaching hospital, and length of stay. Among co-morbidities, atrial fibrillation or fluid and electrolytes imbalance were the most common associated with cost. The authors found that during the period between 2003 and 2012 post cardiac arrest, hospitalizations had a steady rise and associated healthcare costs likely related to increase length of stay, medical procedures and systems of care. In our next paper, Peter Huntjens and associates examined intrinsic interventricular dyssynchrony as a predictor of human dynamic response to cardiac resynchronization. The authors use a cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular or intraventricular activation on resynchronization therapy response that is the change in LV dP/dt max. The simulated change in LV dP to dt max had a range of 1.3 to 26.5% increased considerably with increasing inter ventricular dyssynchrony. In contrast, the isolated effect of intra ventricular dyssynchrony was limited with the change in the LV dP/dt max range and the left ventricle from 12.3 to 18.3% in the right ventricle from 14 to 15.7%. Secondly, electrocardiographic imaging derived activation characteristics of 51 CRT candidates were used to create individual models of ventricular activation in CircAdapt. The model predicted change in LV dP/dt max was close to the actual value in left bundle branch block patients with 2.7% difference between measured and simulated when only intrinsic interventricular dyssynchrony was personalized. Among non left bundle branch block patients a change in LV dP/dt max was systematically over predicted by CircAdapt with a 9.2% difference between measured and simulated. Adding intra ventricular activation to the model did not improve the accuracy of response prediction. The authors found that computer revealed intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT. In the next paper Kenji Kuroki and associates examined the use of voltage limit adjustment of substrate mapping and fast Fourier transform analysis of local ventricular bipolar electrograms during sinus rhythm to predict VT isthmuses. They performed these studies and nine post infarction patients who underwent catheter ablation for total of 13 monomorphic ventricular tachycardias. Relatively higher voltage areas on electroanatomical map or defined as high voltage channels, which were further classified as full or partial if the entire or more than 30% of the high voltage channel was detectable. 12 full high voltage channels were identified in seven of nine patients. Relatively higher fast Fourier transform areas were defined as high frequency channels, which were located on seven of 12 full high voltage channels. Five VT isthmuses or 71% were included in the seven full high voltage channels positive in high frequency channel positive sites. While no VT isthmuses were found in five full high voltage channel positive but high frequency channel negative sites, high frequency channels were identical to 9 out of 16 partial high voltage channels. Eight VT isthmuses or 89% were included in nine partial high voltage channel positive in high frequency channel positive sites, whereas no VTs isthmuses were found in the seven partial high voltage channel positive and high frequency channel negative sites. All high voltage channel positive in high-frequency channel positive sites predicted VT isthmus with a sensitivity of 100% and specificity of 80%. The authors concluded that based on this small series that combined use of voltage, limited adjustment and fast Fourier transform analysis may be useful method to detect VT isthmuses. In the next study, John Whitaker and associates examined the use of lesion index, LSI index, a proprietary algorithm combining contact force, radio-frequency application duration, and RF current. Cardiac CT was used to assess atrial tissue thickness. Ablation lines two to three per animal were created in the right atrium in seven mini pigs with point lesions using 25 watts of energy. Two weeks after the ablation, serial sections of targeted atrial tissue or examine histologically to identify gaps and transmural ablation. LSI guidelines had a lower incidence of histological gaps. Four gaps in the 69 catheter moved or 5.8% compared to ablation using LSI plus two millimeter lines in which there is seven gaps in 33 catheter moves or 21.2% and using LSI plus four millimeter lines in which there are 15 gaps in 23 moves or 65.2% p less than 0.0. The change in LSI was calculated retrospectively is a distance between two adjacent lesions above the mean LSI of the two lesions. Changing LSI values of 1.5 or less were associated with no gaps in transmural ablation. The authors concluded that in this mod of chronic atrial ablation delivery of uninterrupted transmural linear lesions may be facilitated using LSI to guide catheter movement. When change in LSI between adjacent legions is 1.5 millimeters or lower, no gaps in atrial linear lesions should be expected. In our next paper, Matthew Bennett and associate examined whether their response to antitachycardia pacing in patients with ICD could further discriminate ventricular from super ventricular arrhythmias in patients receiving ATP in the RAFT trial. The RAFT trial randomized 1,798 patients with New York Heart Association class two or three heart failure, left ventricular ejection fraction less than or equal to 30%, in QRS duration 120 millisecond or greater, to an ICD plus or a minus cardiac resynchronization. Beginning with 10,916 ATP attempts for 8,150 tachycardia episodes in 924 patients, the author's excluded tachycardias where ATP terminated the episode or were the specific etiology tachycardia was uncertain. In this study, they analyzed 3,676 ATP attempts delivered to 2,046 tachycardia episodes in 541 patients. The authors found that a shorter difference between the post pacing interval is PPI minus TCL, was more likely to be associated with VT than SVT, mean of 138.1 milliseconds for VT and 277.4 milliseconds for SVT p, less than 0.001. A PPI minus TCL value of less than or equal to 300 milliseconds had a sensitivity in 97.4% and a specificity of 28.3% for VT. The authors concluded that specifically the PPI minus TCL following antitachycardia pacing may help distinguish ventricular from supraventricular arrhythmias. In the next study, Shailee Shah and Amr Barakat and associates examined the outcomes after repeat AF ablation. The authors examined 137 patients out of a total of 10,378 patients undergoing Afib ablation who had had initial long-term success defined from recurrent arrhythmias for greater than 36 months off anti-arrhythmic drugs in subsequent underwent repeat ablation for recurrent atrial fibrillation. The median arrhythmia free period that define long-term success was 52 months. In redo-ablations reconnection of at least one of the pulmonary veins was found in 111 or 81% of patients. Additional non PV ablations were performed in 127 or 92.7% of patients. After a mean follow-up of 17 months, 103 patients or 75% were arrhythmia-free, 79 off anti-arrhythmics, and 24 on arrhythmics. The authors found that repeat ablations with re-isolation to the point of veins and modifying the atrial substrate had a good success rate. In the next article Qiongling Wang and associates hypothesized that genetic inhibition of CaMKII oxidation in a mouse model of Duchenne muscular dystrophy can alleviate abnormal calcium homeostasis thus preventing ventricular arrhythmias. The authors tested whether the selective loss of oxidation of the CaMKII effects ventricular arrhythmias in the mouse model of Duchenne muscular dystrophy. Genetic inhibition of ox-CaM kinase II by knocking replacement of the regulatory domain methionines with valines, which we'll call MMVV, prevented ventricular tachycardia in the mdx mice. Confocal calcium imaging of ventricular myocytes, isolated from the mdx MMVV mice revealed normalization of intra-calcium release events compared to myocytes from the mdx mice. Abnormal action potentials as assessed by optical mapping mdx were also alleviated by genetic inhibition of ox-CaMK II. Knockout of the NADPH oxidase regulatory sub-unit P 47 Fox normalized elevated ox-CaMK II, repaired intracellular calcium hemostasis and rescued inducible ventricular arrhythmias in the mdx mice. The authors concluded that inhibition of ROS or ox-CaMK II protects against pro-arrhythmic intracellular calcium handling, preventing ventricular arrhythmias in a mouse model of Duchenne muscular dystrophy. In the next article, Kyohei Marume and Teruo Noguchi and associates examined whether the combination of QRS duration of 120 milliseconds or greater in late gadolinium enhancement is a precise prognostic indicator for the primary endpoint of all cause death and a composite of sudden cardiac death or aborted sudden cardiac death in 531 patients with dilated cardiomyopathy. They also analyzed the association between the combination of late gadolinium enhancement and increased QRS duration in these end points among patients with a class one indication for implantable defibrillator. The author's divided study patients in three groups according to late gadolinium enhancement in QRS duration. Two negative indices that is late gadolinium enhancement negative and narrow QRS, one positive index with either late gadolinium enhancement positive or wide QRS or two positive indices late gadolinium positive and wide QRS and followed them for 3.8 years. Multiple variable Cox regression analysis identified to positive indices as significant predictors of all cause death. A hazard ratio of 4.29 p equals 0.026. Among the 317 patients with a class one indication for ICD, the five year event rate of sudden cardiac death or aborted sudden cardiac death was lowest in the two negative indices groups, 1.4%. With propensity score matching cohorts the two negative indices group had a significant lower event rate of sudden cardiac death or aborted sudden cardiac death than to two other groups hazard ratio 0.2, p equals 0.046. The authors concluded that the combination of late gadolinium enhancement in wide QRS provides additional prognostic stratification compared to late gadolinium enhancement status alone. In the next study, Matthew Sulkin and associates examined whether a novel local impedance measurement on an ablation catheter identifies catheter tissue coupling and is predictive of lesion formation. The author's first studied explanted hearts, 10 swine, and then in vivo 10 swine, using an investigational electro anatomical mapping system that measures impedance from an ablation catheter with mini electrodes incorporated into the distal electrode. Rhythmia and Intellanav, Boston Scientific. Explanted tissue was placed in a warmed 37 degree celsius saline bath mounted on a scale, and the local impedance was measured 15 millimeters away from the tissue to five millimeters of catheter tissue compression at multiple catheter angles. Lesions were created for 31 and 50 watts from 5 to 45 seconds for an N of 70. During in vivo valuation of the local impedance measurements of the myocardium 90 and blood pool 30 were guided by intracardiac ultrasound while operators were blinded to the local impedance data. Lesions were created with 31 and 50 watts for 45 seconds in the ventricle with an n of 72. The local impedance of myocardium, which was 119.7 ohms, was significantly greater than in blood pool 67.6 ohms the p of less than 0.01. Models that incorporate local impedance drop to predict lesion size had better performance that models incorporate force time integral r squared of 0.75 versus r squared of 0.54 and generator impedance drop r squared of 0.2 versus r squared of 0.58. Steam pops displayed a significantly higher starting local impedance and a larger change in local impedance compared to successful RF applications, p less than 0.01. The authors concluded that local impedance recorded for miniature electrodes provides a valuable measure of catheter tissue coupling and the change in local impedance is predictive of lesion formation during RF ablation. In the next paper, Boaz Avitall and associates found that the rising impedance recorded from a ring electrode placed two millimeters from the cryoballoon signifies ice formation covering the balloon surface and indicates ice expansion. The authors studied 12 canines in a total of 57 pulmonary veins, which were targeted for isolation. Two cryoapplications were delivered per vein with a minimum of 90 and a maximum 180 second duration. Cryoapplications was terminated upon reaching a 500 ohm change from baseline. Animals recovered 38 plus or minus six days post procedure, and the veins were assessed electrically for isolation. Heart tissue was histological examined. Extra cardiac structures were examined for damage. Pulmonary vein isolation was achieved in 100% of veins if the impedance reached 500 ohms in 90 to 180 seconds. When the final impedance was between 200 and 500 ohms within 180 seconds of freeze time, pulmonary vein isolation was achieved in 86.8%. For impedance of less than 200 ohms pulmonary vein isolation was achieved in 14%. No extra cardiac damage was recorded. The authors found that impedance rise of 500 ohms at less than 90 seconds with a freeze time of 90 seconds resulted in 100% pulmonary vein isolation. In our final papers Sally-Ann Clur and associates examined left ventricular isovolumetric relaxation time as the potential diagnostic marker for fetal Long QT Syndrome. Left ventricular isovolumetric contraction time, ejection time, left ventricular isovolumetric relaxation time, cycle length, and fetal heart rate were measured using pulse doppler wave forms in fetuses. Time intervals were expressed as percentage of cycle length, and the left ventricular myocardium performance index was calculated. Single measurements were stratified and compared between Long QT Syndrome fetuses and controls. Receiver operator curves were reformed for fetal heart rate in normalized left ventricular isovolumetric relaxation time. A linear mixed effect model including multiple measurements was used to analyze fetal heart rate, the left ventricular iso volume metric relaxation time, and the left ventricular myocardial performance index. There were 33 Long QT fetuses in 469 controls. In Long QT fetuses the left ventricular isovolumetric relaxation time was prolonged in all groups, p less than 0.001, as was the left ventricular isovolumetric relaxation time. The best cutoff to diagnose Long QT syndrome was the normalized left ventricular isovolumetric relaxation time greater than equal to 11.3 at less than or equal to 20 weeks, giving a sensitivity in 92% and a specificity of 70%. Simultaneous analysis of the normalized left ventricular isovolumetric relaxation time and fetal heart rate improved the sensitivity and specificity of Long QT Syndrome, AUC of 0.96. The normalized left ventricular isovolumetric relaxation time, the left ventricular myocardial performance index, and fetal heart rate trends differed significantly between Long QT Syndrome fetuses and controls throughout gestation. The authors concluded that left ventricular volumetric relaxation time is Prolonged QT fetuses. Findings of a prolonged normalize left ventricular isovolumetric relaxation time, and sinus bradycardia can improve the prenatal detection of fetal Long QT Syndrome. That's it for this month, but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcasts On the Beat. Take it away Suraj. Suraj Kapa: Thank you, Paul and welcome back to On the Beat were we will be summarizing hard-hitting articles across the entire electrophysiologic literature. Today we'll be starting within the realm of atrial fibrillation where we're review an article within the realm of anticoagulation and stroke prevention. Quon et al. published in last month's issue of JACC cardiac electrophysiology on anticoagulant use and risk of ischemic stroke and bleeding in patients with secondary atrial fibrillation. It is well known that use of anticoagulation in atrial fibrillation can reduce overall thromboembolic outcomes. However, its role in secondary atrial fibrillation is unclear. Thus, the authors sought to evaluate the effects anticoagulant use on stroke and bleeding risk. Amongst those where atrial fibrillation occurred in the setting of acute coronary syndrome, pulmonary disease, or sepsis. Amongst around 2300 patients evaluated retrospectively there was no evidence of a lower incidence of ischemic stroke among those treated with anticoagulants compared to those who are not. However, anticoagulation was associated with a higher risk of bleeding in those with new onset AF associated with acute pulmonary disease. The authors suggest as a result that there is unclear overall benefit for long-term anticoagulation in patients with presumed secondary atrial fibrillation. The difficulty in assessing this is how to define secondary atrial fibrillation. However, in many studies patients who developed in the setting of acute illness still had a high risk of developing quote unquote clinically significant AF in long-term follow-up. However, this was not necessarily absolute as many patients not necessarily develop AF that could be considered clinically significant. Thus, the clinical question that arises is: how long should we treat a patient with anticoagulation when they have presumed secondary atrial fibrillation. These data seem to suggest that there may be no net overall benefits. In other words, all-comers with secondary atrial fibrillation should not necessarily be forever treated with anti-coagulation. However, this slightly requires clinical trials to evaluate further. Next we delve into the realm of cardiac mapping and ablation where we view an article by Gaita et al. entitled 'Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow-up?', published in Europace last month. While pulmonary vein isolation is a widely accepted approach for treatment of atrial fibrillation, most reported studies review outcomes in terms of freedom of AF over a relatively short time period, generally two to five years. However longer term follow up is inconsistently reported. Gaita et al. sought to review 10 year outcomes amongst 255 patients undergoing ablation in a single center. They noted 52% remainder arrhythmia-free amongst a mixed cohort of both paroxysmal and persistent patients while 10% progressed to permanent atrial fiBrillation. They found that absence of increases in blood pressure, BMI, and fasting glucose was protective against an arrhythmia recurrence. These findings suggest that in a relatively small cohort of patients limited to a single center that even long-term outcomes after pulmonary vein isolation are generally quite good, exceeding 50%. However, future freedom from atrial fibrillation is heavily tied to control of other risk factors. In other words, if a patient is going to have poor control of diabetes, blood pressure, or gain weight, the benefit of their pulmonary vein isolation over long-term follow-up is likely less. These data thus highlight both the potential long-term benefit of PVI, but also the importance of counseling patients regarding the need for continued management and control of future and existing risk factors. Staying within the realm of atrial fibrillation we next review an article by Weng et al. entitled 'Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation' published in last month's issue of circulation. The probability of detecting atrial fibrillation in patients based on clinical factors and genetic risk is unknown. Weng et al. sought to clarify whether a combination of clinical and polygenic risk scores could be used to predict risk of developing atrial fibrillation over long-term followup in the Framingham Heart Study. Amongst 4,600 individuals, 580 developed incident atrial fibrillation and had an overall lifetime risk of developing atrial fibrillation of 37%. Those are the lowest risk tertile based on clinical risk factor burden and genetic predisposition had a lifetime risk of 22% versus 48% in the highest. Furthermore, a lower clinical risk factor burden was associated with delayed atrial fibrillation onset. In order to identify patients with atrial fibrillation, before negative sequelae such as stroke occur, patient and physician understanding of risk and monitoring needs is necessary. The fact is that it will be great to identify every single patient who has atrial fibrillation before they have a negative sequela of that atrial fibrillation such as ischemic stroke. However, performing continuous monitoring of all patients with potential negative sequelae of atrial fibrillation is extraordinarily difficult. The reason is it's excessively costly. We cannot monitor the entire population irrespective of whatever the risk factors are. However, if we're able to identify the highest risk cohorts early on before the atrial fibrillation onsets, this may offer opportunities for use of newer cheaper monitors. The work by Weng et al. suggests one such possible approach combines clinical and polygenic risk scores. Actionability of these data, however, remains to be seen and further validation other cohorts is necessary to clarify generalized ability. The next article we review is published in last month's issue of the Journal of American College of Cardiology by Lopes at al. entitled 'Digoxin and Mortality in Patients With Atrial Fibrillation. Lopes et al. sought to evaluate the impact of the Digoxin on mortality in patients with atrial fibrillation and the association with the Digoxin serum concentration and heart failure status. They value this association in over 17,000 patients. At baseline 32% were receiving Digoxin. Baseline Digoxin use did not associate with risk of death, but even in these patients a serum concentration of greater than 1.2 nanograms per milliliter was associated with a 56% increase in mortality risk. For each .5 nanogram per milliliter increase in oxygen concentration the hazard ratio increased by 19% for overall mortality. This was irrespective of heart failure status. Furthermore, in patients who are newly started in Digoxin over the follow-up period, the risk and death and sudden death was higher. These data suggests a significant risk associated with Digoxin use for management of atrial fibrillation irrespective of heart failure status. Furthermore, serum valleys above 1.2 require close consideration of dose de-escalation. Whether there is any optimal dose, however, from the study is unclear. These data amongst a host of prior data strongly suggest again strategic use of Digoxin principally for the management of atrial fibrillation. Moving on within the realm of atrial fibrillation, we review an article published in last month's issue of Circulation Research by Yan et al. entitled Stress Signaling JNK2 Crosstalk with CaMKII Underlies Enhanced Atrial Arrhythmogenesis. In this more acellular based study the mechanism underlying atrial arrhythmogenesis associated with aging was evaluated. Yan et al. sought to figure out whether the stress response JNK in calcium mediated arrhythmias might contribute to atrial arrhythmogenesis in aged transgenic mouse models. They demonstrated significant increased activity of JNK2 and aging atria, those furthermore associated with rhythmic remodeling. This association was mediated through CaMKII and ryanodine receptor channel function, with activation of the former leading to increased calcium leak mediated by the ladder. This in turn related to increase atrial fibrillation likelihood. Identifying novel targets for atrial fibrillation therapy is critical. Given atrial fibrillation is a complex disease process related to a multitude of risk factors it can be assumed that the contribution of any single factor may be mediated through distinct mechanisms. Aging in particular as well regarded, but considered to be non-modifiable risk factor for atrial fibrillation. Identifying genes or pathways, the immediate aging associated fibrillation, may take the risk of aging as no longer a non-modifiable thing. The finding of the significance of JNK2 and associate downstream effects with AF risks and aging hearts may hold potential in offering unique therapeutic targets. Finally, within the realm of atrial fibrillation, we're viewing article by Chen et al. in last month's issue of the Journal of the American Heart Association entitled Association of Atrial Fibrillation With Cognitive Decline and Dementia Over 20 Years: The ARIC-NCS Study. Multiple studies have suggested a significant association between atrial fibrillation risk of dementia. However, these studies have limited time follow-up and were often done and predominantly white patients. Thus, the authors sought to use the data from ARIC, the Atherosclerosis Risk in Communities Neurocognitive Study, to assess the risk of cognitive decline associated with atrial fibrillation. Amongst over 12,000 participants, a quarter of whom are black and half of whom are white, they noted 2100 patients developed atrial fibrillation and 1,150 develop dementia over a 20 year follow up period. There was a significantly greater risk of cognitive decline amongst those who developed atrial fibrillation. In turn incident atrial fibrillation for the follow-up period was associated with a higher risk of dementia even after adjusting for other clinical and cardiovascular risk factors such as incidents that ischemic stroke. These data further strengthened prior evidence of a direct link between atrial fibrillation and risk of cognitive decline and dementia. Understanding this long-term risk raises the need to additionally identify approaches to prevent this occurrence, which in turn is dependent on understanding the underlying mechanisms. The finding that the risk of cognitive decline dementias independent of ischemic stroke events raises concern that either subclinical micro-embolic events or other factors may be playing a role in this risk and in turn raises question as to how best to prevent them. Until better understood, however, the question of whether the association is causal remains to be seen. Changing gears yet again, we now delve into the realm of ICDs, pacemakers and CRT. Published in last month, issue of Heart Rhythm Tarakji et al. published a paper entitled 'Unrecognized venous injuries after cardiac implantable electronic device transvenous lead extraction.' Overall risk of transvenous lead extraction includes that of potentially fatal venous laceration. The authors sought to evaluate the incidence of venous injury that may be unrecognized based on microscopic study of extracted leads. Amongst 861 leads obtained from 461 patients they noted 80 leads or almost 9%. Amongst 15% of patients showed segments vein on the lead body, most of which were transmural including the tissue layer. However, in terms of clinical significance, only 1% had need for emergent surgical intervention for clinically significant venous laceration. Risk factors for having the entire vein on the lead included age of lead, ICD leads, and the use of the laser sheath. These findings suggest that there may be a high incidence of subclinical venous injury after lead extraction though rarely resulting clinically apparent sequelae. As would be expected, venous injury, including transmural removal of portions of the vein traversed by the lead, was more common amongst older leads, which generally more often require laser sheets and ICD leads. The question is however, whether this carries any direct clinical implications. One they may be considered is the potential additive risk of an advancing new lead through the same venous channel, particularly in the setting of potential transmural venous injury that already exists. Next in last month's issue of Heart Rhythm we review an article by Sharma at al. entitled 'Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience.' The use of resynchronization therapy for treatment of patients with heart failure and wide QRS has been shown to offer morbidity and mortality benefits. However, many patients maybe non-responders, and recent studies on His bundle pacing of suggested potential clinical benefits. His bundle pacing essentially only requires one pacing catheter attached within the region of the His bundle Sharma et al. sought to evaluate the safety and success rates of His bundle pacing for patients who have either failed standard resynchronization therapy or in whom most tried as a primary intervention. They noted His bundle pacing was successful in 90% of patients with reasonable myocardial and His bundle capture thresholds. Patients in both groups exhibits significant narrowing of QRS morphology and improvement in left ventricular ejection fraction from a mean of 30 to 43%. However, a total of seven patients had lead related complications. These database on a retrospective analysis of two types of patients, those failing standard biventricular therapy, and those on whom his bundle pacing was attempted as a primary modality suggest overall safety and efficacy in a handful of experienced centers. The promise of His bundle pacing is that a may allow for more effective resynchronization than standard approaches. The high rate of success suggests that His bundle pacing maybe both safe and reasonable to pursue. However randomized trials across more centers are needed to fully prove its benefit, particularly as a primary modality of treatments. Next we review ICDs and chronic kidney disease. In last month's issue of JAMA cardiology by Bansal at al. entitled 'Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease.' While the benefit of ICDs in patients with low EF is widely recognized, modifying factors that may increase risk of death are not as well defined. These include things like advanced age and chronic kidney disease. Bansal et al. sought to evaluate long-term outcomes and ICD therapy in patients with chronic kidney disease. In retrospective study of almost 5,900 ambulatory patients amongst whom 1550 had an ICD, they found no difference in all cause mortality. However, ICD placement was associated with an increased risk of subsequent hospitalization due to heart failure or any cause hospitalization. In light of recent studies such as DANISH the robust sense of ICD benefit is being questioned. One of the thoughts for the absence of similar benefit to prior studies lies in the improving care of ambulatory heart failure patients. In patients with chronic kidney disease several questions rises to the risk with ICD, including infectious risk in dialysis patients and the concomitant mortality risk with renal dysfunction. The author suggested in retrospective study, no incremental benefit of ICDs in patients with chronic kidney disease and perhaps some element of added risk is related to hospitalization. However, this study has several limitations. It is retrospective and many patients received ICDs may have been perceived to be sicker in some way. Thus care must be taken in interpretation, but consideration of randomized studies to adjudicate benefit are likely necessary. Finally, within the realm of devices, we reviewed an article by Tayal et al. entitled "Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS Complexes.' publishing the Journal of American College of Cardiology last month. Several parameters have been stressed to identify benefit of resynchronization therapy in patients with wide QRS include cross correlation analysis with tissue doppler imaging. However, many patients may have evidence in mechanical dyssynchrony even in the absence of an apparent wide QRS thus Tayal et al. sought to evaluate the benefit of resynchronization therapy amongst 807 patients with heart failure and a narrow QRS mean criteria in a randomized study. Of the 807 46% had delayed mechanical activation. Those without delay mechanical activation had underwent we standardization therapy and were associated with worse overall outcomes likely due to new delayed mechanical activation potentially related to CRT pacing. These data support the absence of a role for resynchronization therapy in patients with a narrow QRS. This is expected as resynchronization therapy likely offers the most benefit in patients with mechanical dyssynchrony that results from electrical dyssynchrony. Since by its very nature resynchronization therapy relies on non physiologic cardiac pacing thus compared to normal cardiac activation the nature of resynchronization pacing is desynchronization. These data support the absence of a role for resynchronization therapy in patients with heart failure and narrow QRS complexes. Moving on to cellular electrophysiology we review an article by Kozasa et al. published in last month's issue of Journal of Physiology entitled 'HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node.' Heart rate is controlled by an interplay between sympathetic and parasympathetic components. In turn HCN4 abnormalities have been implicated in congenital sick sinus syndrome. The authors sought to clarify the contribution of HCN4 to sinus node autonomic regulation. They created a novel gain-of-function mouse where the HCN4 activity could be modulating from zero to three times normal. They then evaluated ambulatory heart-rate variability and responsive heart rate to vagus nerve stimulation. They found HCN4 over-expression did not increase heart rate, but attenuated heart-rate variability. It also attenuated bradycardic response to vagus nerve stimulation. Knockdown of HCN4 in turn lead to sinus arrhythmia and enhanced parasympathetic response. These data suggest HCN4 attenuates sinus node response to vagal stimuli thus stabilizing spontaneous firing of the node. The clinical application of this remain to be seen but are maybe important in that they highlight a mechanism for a heretofore poorly understood mechanism for how exactly HCN4 abnormalities may lead to sick sinus syndrome. Within the realm of ventricular arrhythmias we highlighted a number of articles published this past month. The first article we review was published in last month's issue of JACC clinical electrophysiology, entitled characterization of the electrode atomic substrate and cardiac sarcoidosis: correlation with imaging findings of scarring inflammation published by [inaudible 00:41:40] et al. In patients with cardiac sarcoidosis one of the questions is how to define the electronic atomic substrate, particularly before we entered the electrophysiology laboratory. Both active inflammation and replacement fibrosis maybe be seen in patients. The authors evaluated in 42 patients with cardiac sarcoidosis, the association between an abnormal electrograms and cardiac imaging findings including PET and Computed Tomography, as well as Cardiac MRI. They noted that amongst these 40 patients, a total of 21,000 electrograms were obtained, and a total of 19% of these were classified as abnormal. Most of the abnormalities occurred in the basal paravalvular segments and intraventricular septum. They further noted that many of these abnormalities in terms of electrograms were located outside the low voltage areas, particularly as it relates to fractionation. In about 90% of patients they notice late gadolinium enhancements and they noted abnormal FDG uptakes suggesting active inflammation in about 48%. However, it should be noted that only 29 of the 42 patients underwent cardiac imaging. Segments with abnormal electrograms tended to have more late gadolinium enhancement evidence scar transmurality, and also they noted that the association of abnormal PET scan did not necessarily occur with abnormal electrograms. Thus, they concluded that in patients with cardiac sarcoidosis and ventricular tachycardia pre-procedural imaging with cardiac MRI could be useful in detecting electroanatomic map abnormalities that may in turn be potential targets for substrate ablation. However, they were more likely associated with more scar transmurality and lower degrees of inflammation on PET scanning. These data are important in that they highlight potential non-invasive means by which to understand where substrate might occur in patients with the cardiac sarcoidosis. It is well recognized that cardiac sarcoidosis is associated with increased risk of ventricular arrhythmias. These risks have increased ventricular arrhythmias, might be targetable with ablation. Newer therapies might even offer non invasive means by which to perform ablation in patients best. Thus if we could identify non based on mechanisms of identifying the substrate, this will be even more critical. The critical findings of this particular paper lie in noting that most of the abnormalities still is in intra ventricular sePtum in basal segments, and also that it is MRI in late gadolinium enhancement and associates more with the abnormal electrograms. Interestingly, the absence of inflammation correlating with the presence of more abnormal electrograms suggests that it is not so much the act of inflammation as being reflected in the endocardial map, but the existence of scar. Next, again within JACC clinical electrophysiology we review an article by Porta-Sánchez et al. entitled 'Multicenter Study of Ischemic Ventricular Tachycardia Ablation With Decrement Evoked Potential Mapping With Extra Stimulus.' The authors sought to conduct a multicenter study of decrement evoked potential base functional tech ventricular tachycardia substrate modification to see if such mechanistic and physiologic strategies could result in reduction in VT burden. It is noted that really only a fraction of the myocardium in what we presume to be substrate based on the presence of low voltage areas are actually involved in the initiation and perpetuation of VT. Thus if we can identify the critical areas within the presumed substrate for ablation, this would be even a better way of potentially honing in on our targets. They included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping fractionated late potentials were targeted and an extra stimulus was provided to determine which display decrements. All patients underwent DEEP focus ablation with elimination being correlated with VT non-inducibility after radio-frequency ablation. Patients were predominantly male, and they noted that the specificity of these decrement evoked potentials to detect the cardiac isthmus for VT was better than that of using late potentials alone. They noted 15 of 20 patients were free of any VT after ablation of these targets over six months of follow-up, and there was a strong reduction in VT burden compared to six months pre ablation. They concluded that detriment evoked potential based strategies towards ablation for ventricular tachycardia might identify the functional substrate and those areas most critical to ablation. They in turn regarded that by its physiologic nature it offers greater access to folks to ablation therapies. This publication is important in that it highlights another means by which we can better hone in on the most critical regions for substrate evaluation in patients with ventricular tachycardia. The fact is more extensive ablation is not necessarily better and might result in increased risk of harm if we think about the potential effects of longer ablations or more ablation lesions. Thus if we could identify ways of only targeting those areas that are most critical to the VT circuits, we could perhaps short and ablation procedural time, allow for novel ways of approaching targeted ablation with limited amounts of ablation performed, or perhaps even improve overall VT outcomes by knowing the areas that are most critical to ensure adequate ablation therapy provided. However, we need to understand that this is still a limited number of patients evaluated in a non randomized manner. Thus whether or not more extensive ablation performed might have been better is as of yet unclear Staying within the realm of ventricular tachycardia we review an article published in last month's issue of Heart Rhythm by Winterfield et al. entitled the 'Impact of ventricular tachycardia ablation on healthcare utilization.' Catheter ablation of atrial tachycardia has been well accepted to reduce recurrent shocks in patients with ICDs. However, this is a potentially costly procedure, and thus effect on overall long-term health care utilization remains to be seen. The authors sought to evaluate in a large scale real world retrospective study the effect of VT ablation on overall medical expenditures in healthcare utilization. A total 523 patients met study inclusion criteria from the market scan database. After VT ablation median annual cardiac rhythm related medical expenditures actually decreased by over $5,000. Moreover the percentage of patients with at least one cardiac rhythm related hospitalization an ER visit decreased from 53 and 41% before ablation respectively, to 28 and 26% after ablation. Similar changes we're seeing in number of all cause hospitalizations and ER visits. During the year before VT ablation interestingly there was an increasing rate of healthcare resource utilization, but a drastic slowing after ablation. These data suggests that catheter ablation may lead to reduced hospitalization in overall healthcare utilization. The importance of these findings lies in understanding why we do the things we do. We can provide a number of therapies to patients, but we seek two different effects. One is the individual effect of improving their particular health. The second thing is trying to avoid increasing healthcare expenditures on a population level and making sure resources are utilized. If we can reduce recurrent hospitalizations and overall healthcare expenditure in patients by providing a therapy in addition to provide individual benefit, this is the optimal situation. These data suggests that VT ablation might provide such a benefits, that in fact it reduces overall healthcare utilization while improving overall outcomes. Next and finally within the realm of ventricular arrhythmias, we review more on the basic side the role of Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias, published by Verdonschot et al. in last month's issue of European Heart Journal. It is known now that truncating Titin variants might be the most prevalent genetic cause of dilated cardiomyopathy. Thus, the authors sought to study clinical parameters and long term outcomes related to Titin abnormalities in dilated cardiomyopathy. They reviewed 303 consecutive and extensively phenotype dilated cardiomyopathy patients who underwent cardiac imaging, Holter monitoring, and endomyocardial biopsy and in turn also underwent DNA sequencing of 47 cardiomyopathy associated genes. 13% of these patients had Titin abnormalities. Over long-term followup they noted that these patients had increased ventricular arrhythmias compared to other types of dilated cardiomyopathy, but interestingly, they had similar survival rates. Arrhythmias in those Titin abnormal patients were most prominent in those who were subjected to an additional environmental trigger, including viral infection, cardiac inflammation, other systemic disease or toxic exposure. They also noted the cardiac mass was relatively reduced in titan admirable patients. They felt that all components of the mitochondrial electron transport chain we're simply up-regulated in Titin abnormal patients during RNA sequencing and interstitial fibrosis was also augmented. As a result, they concluded that Titin variant associated dilated cardiomyopathy was associated with an increased risk of ventricular arrhythmias, and also with more interstitial fibrosis. For a long time we have reviewed all non ischemic cardiomyopathy as essentially equal. However, more recent data has suggested that we can actually hone in on the cause. In turn, if we hone in on the cause, we might be able to understand the effects of specific therapies for ventricular arrhythmias based on that underlying cause. Patchy fibrosis might not be as amenable, for example, to ablation as discreet substrate that we might see in infarct related VT. Understanding the relative benefit in very specific types of myopathies might hold benefit in understanding how to, one, risk stratify these patients, and two, understand what type of therapy, whether pharmacologic or ablative, might result in greatest benefit to the patients. Changing gears entirely now to the role of genetics, we review multiple articles in various genetic syndromes published this past month. First, we reviewed an article by Providência et al. published in the last month's issue of heart entitled 'Impact of QTc formulae in the prevalence of short corrected QT interval and impact on probability and diagnosis of short QT syndrome.' The authors sought to assess the overall prevalence of short corrected QT intervals and the impact on diagnosis of short QT syndrome using different methods for correcting the QT interval. In this observational study they reviewed the sudden cardiac death screening of risk factors cohorts. They then applied multiple different correction formulae to the ECGs. They noted that the prevalence of individuals with the QTc less than 330 and 320 was extremely low, namely less than .07 and .02% respectively. They were also more frequently identified using the Framingham correction. The different QTc correction formulae could lead to a shift of anywhere from 5 to 10% of individuals in the cohort overall. They further noted, that based on consensus criteria, instead of 12 individuals diagnosed with short gut syndrome using the Bazett equation, a different number of individuals would have met diagnostic criteria with other formulae, 11 using Fridericia, 9 with Hodges, and 16 using the Framingham equation. Thus, they noted that overall the prevalence of short QT syndrome exceedingly low and an apparently healthy adult population. However, reclassification as meeting criteria might be heavily dependent on which QT correction formula is used. The importance of these findings is that not all QTs are created equal. Depending on how you compute the QT interval in which formula to use may affect how you actually risk characterize a patient. Unfortunately, these data do not necessarily tell us which is the right formula, but this highlights that it might be relevant to in the future evaluate the role of different formulae and identifying which is the most necessary to classify a patient. Moving on to an article published in last month's issue of the journal of clinical investigation by Chai et al. we review an article entitled 'Physiological genomics identifies genetic modifiers of Long QT Syndrome type 2 severity.' Congenital Long QT Syndrome is a very well recognized, inherited channelopathy associated life-threatening arrhythmias. LQTS type 2 is specifically caused by mutations in casein to encoding the potassium channel hERG. However, even with the mutation not all patients exhibit the same phenotype. Namely some patients are more at risk of life threatening arrhythmias in spite of having the same mutation as others who do not exhibit the same severity phenotype. The authors sought to evaluate whether specific modifiable factors within the remaining genetic code might be modifying the existing mutation. Thus, they sought to identify contributors to variable expressivity in an LQT 2 family by using induced pluripotent stem cell derived cardiomyocytes and whole exome sequencing in a synergistic manner. They found that patients with severely effected LQT 2 displayed prolonged action potentials compare to sales from mildly effected first-degree relatives. Furthermore, stem cells derived from patients were different in terms of how much L-type calcium current they exhibited. They noted that whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2 in those patients with more severe phenotypes in whom greater L-type calcium current was seen. This suggests that abnormalities or even polymorphisms in other genes might be modifying the risk attributed to by mutations in the primary gene. This showcases the power of combining complimentary physiological and genomic analysis to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. This is extraordinarily critical as we understand on one level that when we sequence a monogenic disorder that there might exist variants of uncertain significance, namely they have not been classified as disease causing, but could be. In turn, we also recognize that mutations in a family might effect different relatives differently. However, why this is has been relatively unclear. If we can understand and identify those patients who are most at risk of dangerous abnormal rhythms, this will be useful in how much to follow them, and what type of therapy to use in them. The fact that other genes might modify the risk even in the absence of specific mutations, suggests that novel approaches to characterizing the risk might help for the risk modified patients classification in general. Clinical use, however, remains to be seen. Moving on from long QT, we evaluate 'The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy' noted in last month's issue of the Journal of American College of Cardiology and published by Papadakis et al. It is well known, the negative autopsies are not uncommon in patients, however, families might be wondering how at risk they are. Thus, the authors sought to assess the impact of systematic ajmaline provocation testing using high right precordial leads on the diagnostic yield Brugada syndrome in a large cohort of Sudden Arrhythmic Death syndrome families. Amongst 303 families affected by Sudden Arrhythmic Death Syndrome evaluation was done to determine whether or not there was a genetic inherited channelopathy cause. An inherited cardiac disease was diagnosed in 42% of the families and 22% of relatives Brugada syndrome was the most prevalent diagnosis overall amongst 28% of families. Ajmaline testing was required, however, to unmask the Brugada Syndrome in 97% of diagnosed individuals. Furthermore, they use of high right precordial leads showed a 16% incremental diagnostic yield of ajmaline testing for diagnosing Brugada syndrome. They further noted that a spontaneous type 1 regard or pattern or a clinically significant rhythmic event developed in 17% of these concealed regardless syndrome patients. The authors concluded the systematic use of ajmaline testing with high right precordial leads increases the yield of Brugada Syndrome testing in Sudden Arrhythmic Death Syndrome families. Furthermore, they noted that assessments should be performed in expert centers or patients could also be counseled appropriately. These findings are important and one of the big questions always becomes how aggressively to test family members of patients or of deceased individuals who experienced sudden arrhythmic death. Many of these patients have negative autopsies, and genetic autopsy might not be possible due to lack of tissue or blood products that can be adequately tested. The data here suggest that amongst a group of 303 sudden arrhythmic death, families that Brugada Syndrome is by far the most frequent diagnosis. If an inherited cardiac disease was identified. In turn, it is not ECG alone or echo alone that helps identify them, but requires drug provocation testing in addition to different electrode placements. Whether or not this will consistently offer benefit in patients in general or my result in overcalling remains to be seen next within the realm of genetic predisposition. We view an area where we don't know if there's a genetic predisposition in article published by Tester et al. entitled Cardiac Genetic Predisposition in Sudden Infant Death Syndrome in last month's issue of the journal of american college of cardiology. Sudden Infant Death Syndrome is the leading cause of post-neonatal mortality and genetic heart diseases might underlie some cases of SIDS. Thus the authors sought to determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for Sudden Infant Death Syndrome. They study the largest cohort to date of unrelated SIDS cases, including a total of 419 individuals who underwent whole exome sequencing and targeted analysis for 90 genetic heart disease susceptibility genes. Overall, 12.6% of these cases had at least one potentially informative genetic heart disease associated variants. The yield was higher in those mixed European ancestry than those of European ancestry. Infants older than four months were more likely to host a potentially informative gene. Furthermore, they noted that only 18 of the 419 SIDS cases hold a [inaudible 01:01:26] or likely pathogenic variant. So in other words, only 4% of cases really had a variant that they could say was distinctly pathogenic or likely pathogenic. Thus, overall, the minority of SIDS cases have potentially informative variant in genetic heart disease susceptibility gene, and these individuals were mostly in the 4 to 12 month age group. Also, only 4% of cases had immediately clinically actionable variance, namely a variant, which is well recognized as pathogenic and where we could actually say that a specific therapy might have had some effect. These findings can have major implications for how best to investigate SIDS cases in families. It might suggest that SIDS cases where the individual was older, nearly 4 to 12 months of age might have a greater yield in terms of identifying variance. While this might not affect the deceased in fit, it might affect, families are planning on having another child in whom a variant can be identified. Finally, within the realm of genetics, we review an article published in last month's issue of Science Advances by Huang. et al. entitled 'Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations'. Mutations that induce loss of function of human KCNQ1 underlie the Long QT Syndrome type 1. While hundreds of mutations have been identified the molecular mechanism by which they result in impaired function are not as well understood. The authors sought to investigate impact of 51 specific variants located within the voltage sensor domain and emphasized effect on cell surface expression, protein folding, and structure. For each variant efficiency of trafficking of the plasma membrane, impact of proteasome inhibition, and protein stability were evaluated. They noted that more than half of the loss of function mutations were seen to destabilized structure of the voltage sensor domain, generally accompanied by mistrafficking and degradation by the proteasome. They also noted that five of the folding defective Long QT Syndrome mutant sites were located in the S0 helix, where they tend to interact with a number of other loss of function mutation sites in other segments of the voltage sensor domain. They suggested these observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilized KCNQ1 overall. They also note the importance of these findings is that mutation-induced destabilization of membrane proteins may be a more common cause of disease functioning in humans. The importance of these findings lies in better understanding why specific mutations lead to appa
We meet up with Robbie, the founder of Fall Down Gallery, a prominent shop in Centretown with great clothes and where artists can put there work up. It also hosts many parties and is just a great non-traditional retail shop that is always evolving. We talk more about his art, how he started FDG, tips for other entrepreneurs and much more! Music this week from Foster!
We meet up with Robbie, the founder of Fall Down Gallery, a prominent shop in Centretown with great clothes and where artists can put there work up. It also hosts many parties and is just a great non-traditional retail shop that is always evolving. We talk more about his art, how he started FDG, tips for other entrepreneurs and much more! Music this week from Foster!
Костя Станкевич рассказал про свои Flash и мобильные игры, про опыт запуска проекта с издателем и попытку самиздата на iOS. Содержание: [00:30] — Представляю гостя. Первые проекты. [04:00] — Starlight. [08:15] — Blueprint3D и Armor Games. Переход с Flash на iOS. [12:45] — Мобильная версия Blueprint3D. FDG. [20:45] — Средства разработки. [21:15] — Место жительства, взаимоотношения с другими разработчиками. [22:50] — Обновление Blueprint3D. [26:15] — Blueprint3D для Android на Unity3D. [29:25] — Google Play. Amazon Kindle. [34:20] — Mac App Store. [35:10] — Самиздат на iOS с Numerity. Идея игры. Разработка. [39:30] — Плюсы и минусы работы с издателем. [49:10] — Маркетинг на iOS своими руками. Этапы, материалы, работа с прессой. [72:15] — Результаты запуска. [74:45] — Локализация. [76:45] — Особенности работы с прессой. [81:15] — Ошибки допущенные при издательстве Numerity. [87:17] — Организация бизнеса и легализация дохода в реалиях СНГ. [98:30] — Отношение к Free-to-play. [99:50] — Планы на будущее. [102:30] — Совет начинающему разработчику. Обсудить подкаст на gamedevblogs.ru: http://gamedevblogs.ru/blog/podcast/1402.html
ecancer reporter Peter Goodwin talks to Dr Yanina Dockx at the 2013 IMPAKT meeting in Brussels. Aberrant activation of the PI3K-Akt-mTOR pathway is an important driver of resistance to HER2 targeted therapies and is involved in glucose homeostasis. 18F-FDG-PET has been proposed for early response assessment for targeted therapies, but knowledge on the effects of blocking this pathway on FDG uptake dynamics is limited. The study investigated the effect of pharmacological PI3K-Akt-mTOR blockade on in vitro FDG uptake in HER2 breast cancer cells resistant to trastuzumab. Blockade of PI3K-Akt-mTOR in trastuzumab resistant HER2 breast cancer was found to affect in vitro 18F-FDG uptake in transient and opposite ways, depending on the pharmacological target and duration of treatment. Therefore, further validation is necessary to elucidate the cellular mechanisms involved in tracer uptake prior to routine clinical use for early response assessment.
Background: This study compared manually delineated gross tumour volume (GTV) and automatically generated biological tumour volume (BTV) based on fluoro-deoxy-glucose (FDG) positron emission tomography (PET)/CT to assess the robustness of predefined PET algorithms for radiotherapy (RT) planning in routine clinical practice. Methods: RT-planning data from 20 consecutive patients (lung-(40%), oesophageal-(25%), gynaecological-(25%) and colorectal (10%) cancer) who had undergone FDG-PET/CT planning between 08/2010 and 09/2011 were retrospectively analysed, five of them underwent neoadjuvant chemotherapy before radiotherapy. In addition to manual GTV contouring, automated segmentation algorithms were applied-among these 38%, 42%, 47% and 50% SUVmax as well as the PERCIST total lesion glycolysis (TLG) algorithm. Different ratios were calculated to assess the overlap of GTV and BTV including the conformity index and the ratio GTV included within the BTV. Results: Median age of the patients was 66 years and median tumour SUVmax 9.2. Median size of the GTVs defined by the radiation oncologist was 43.7 ml. Median conformity indices were between 30.0-37.8%. The highest amount of BTV within GTV was seen with the 38% SUVmax algorithm (49.0%), the lowest with 50% SUVmax (36.0%). Best agreement was obtained for oesophageal cancer patients with a conformity index of 56.4% and BTV within GTV ratio of 71.1%. Conclusions: At present there is only low concordance between manually derived GTVs and automatically segmented FDG-PET/CT based BTVs indicating the need for further research in order to achieve higher volumetric conformity and therefore to get access to the full potential of FDG-PET/CT for optimization of radiotherapy planning.
This interview by medical oncologist Dr. Jack West of Dr. David Djang, nuclear medicine expert in Seattle, covers the general principles and clinical utility of PET scans in lung cancer and other aspects of oncology.
This interview by medical oncologist Dr. Jack West of Dr. David Djang, nuclear medicine expert in Seattle, covers the general principles and clinical utility of PET scans in lung cancer and other aspects of oncology.
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 01/07
2 SUMMARY Pathologically-anatomical and immunhistochemistric investigation of ischemic myocardium in the pig Background: Different degrees of histological alteration have been seen in hibernating myocardium. Hibernation is associated with structural myocardial changes, which involve both the cardiomyocytes and the cardiac interstitium. The purpose of this study is to investigate the effects of chronic myocardial ischemia on histological patterns to understand the underlying mechanism of hibernation. Methods: A model of ischemic injury was produced in 16 pigs (German land breed) by placement of a modified stent graft in the left anterior descending artery (LAD), which initially produced 75% stenosis, followed by a slow complete occlusion. Wall motion abnormalities were investigated by Magnetic Resonance Imaging (MRI) and ultrasound images at day 7 after implantation. Metabolism and perfusion were imaged by Positron Emission Tomography (PET) at day 7 (group 1) and at day 28 (group 2). After PET images the animals were sacrificed and tissue samples were taken for histology. Results: Viability in PET is defined by a relative decrease in perfusion in an area where there is a relative increase in FDG (fluorodeoxyglucose) concentration. This is often referred to as a “mismatch” pattern. In the study nearly all pigs showed this “mismatch” in the LAD area. The following significant results could be found in the mismatched samples: the accumulation of collagen (0,12 ± 0,12 %, p < 0,05) in LAD samples compared to those taken from remote area (0,02 ± 0,02 %) and glycogen rich perinuclear zones in LAD samples (0,06 ± 0,03 %, p < 0,05). Despite the difficulties of reproducing a long-term hibernating myocardium in an animal model, one pig (No.8) demonstrated physiological alterations that can be compared to those of human beings with hibernating myocardium. After 28 days the artery of the pig was completely occluded. A mismatch was determined by PET, and wall motion abnormalities were present. Furthermore in cells which were exposed to a repetitive ischemia, a small degree of fibrosis and glycogen richness were shown. Conclusion: In contrast to various short-term hibernating myocardium models, no equivalent model exists for long-term hibernating myocardium over a time period of weeks or months yet. For this reason, the complete mechanism of chronic hibernating myocardium is still unclear. The fluent transition of the different heart failure up to the infarct as seen in the clinic reflect the dynamic process, the interindividuell differences and last but not least the reduced compensation abilities of the heart. Due to this it is difficult to find a matching in-vivo model that shows the same mechanism as humans. Therefore every small and large animal model is helpful for clarification.
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