Podcasts about fdg pet

CardioNerds (Dr. Rick Ferraro and Dr. Dan Ambinder) join Dr. Sri Mandava, Dr. David Meister, and Dr. Marissa Donatelle from the Columbia University Division of Cardiology at Mount Sinai Medical Center in Miami. Expert commentary is provided by Dr. Pranav Venkataraman.   They discuss the following case involving a patient with cardiac sarcoidosis presenting as STEMI:  A 57-year-old man with a history of hyperlipidemia presented with sudden onset chest pain. On admission, he was vitally stable with a normal cardiorespiratory exam but appeared in acute distress and was diffusely diaphoretic. His ECG revealed sinus rhythm, a right bundle branch block (RBBB), and ST elevation in the inferior-posterior leads. He was promptly taken for emergent cardiac catheterization, which identified a complete thrombotic occlusion of the mid-left circumflex artery (LCX) and large obtuse marginal (OM) branch, with no underlying coronary atherosclerotic disease. Aspiration thrombectomy and percutaneous coronary intervention (PCI) were performed, with one drug-eluting stent placed. An echocardiogram showed a left ventricular ejection fraction (EF) of 31%, hypokinesis of the inferior, lateral, and apical regions, and an apical left ventricular thrombus. The patient was started on triple therapy. A hypercoagulable workup was negative. A cardiac MRI was obtained to further evaluate non-ischemic cardiomyopathy. In conjunction with a subsequent CT chest, the results raised suspicion for cardiac sarcoidosis with systemic involvement. In view of a reduced EF and significant late-gadolinium enhancement, electrophysiology was consulted to evaluate for ICD candidacy. A decision was made to delay ICD implantation until a definitive diagnosis of cardiac sarcoidosis could be established by tissue biopsy. The patient was started on HF-GDMT and discharged with a LifeVest. Close outpatient follow-up with cardiology and electrophysiology was arranged.  US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Cardiac Sarcoidosis Presenting as STEMI Cardiac sarcoidosis can present with a variety of symptoms, including arrhythmias, heart block, heart failure, or sudden cardiac death. Symptoms can be subtle or mimic other cardiac conditions.  Conduction abnormalities, particularly AV block or ventricular arrhythmias, are common and may be the initial indication of cardiac involvement with sarcoidosis.  The additive value of Echocardiography, FDG-PET, and cardiac MR is indispensable in the diagnostic workup of suspected cardiac sarcoidosis.  Specific role of MRI/PET: Both cardiac MRI and FDG-PET provide a complementary role in the diagnosis of cardiac sarcoidosis. Cardiac MRI is an effective diagnostic screening tool with fairly high sensitivity but is limited by its inability to decipher inflammatory (“active” disease) versus fibrotic myocardium. FDG-PT helps to make this discrimination, refine the diagnosis, and guide clinical management. Ultimately, these studies are most useful when interpreted in the context of other clinical information.  Primary prevention of sudden cardiac death in cardiac sarcoidosis focuses on risk stratification, with ICD placement for high-risk patients. For patients awaiting definitive diagnosis, a LifeVest may be used as a temporary measure to protect from sudden arrhythmic events until an ICD is placed.  Notes - Cardiac Sarcoidosis Presenting as STEMI 1. Is STEMI always a result of coronary artery disease?  By definition, a STEMI is an acute S-T segment elevation myocardial infarction. This occurs when there is occlusion of a major coronary artery, which results in transmural ischemia and damage,

Neuroimaging is a tool to classify and ascertain the etiology of epilepsy in people with first or recurrent unprovoked seizures. In addition, imaging may help predict the response to treatment. To maximize diagnostic power, it is essential to order the correct imaging sequences. In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Christopher T. Skidmore, MD, author of the article “Neuroimaging in Epilepsy,” in the Continuum February 2025 Epilepsy issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of clinical neurology at the University of California, San Francisco Dr. Skidmore is  an associate professor of neurology and vice-chair for clinical affairs at Thomas Jefferson University, Department of Neurology in Philadelphia, Pennsylvania. Additional Resources Read the article: Neuroimaging in Epilepsy Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @ctskidmore  Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Christopher Skidmore about his article on neuroimaging in epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast, Dr Skidmore. Would you please introduce yourself to our audience?  Dr Skidmore: Thank you for having me today. I'm happy to talk to you, Dr Berkowitz. My name is Christopher Skidmore. I'm an associate professor of neurology at Thomas Jefferson University in Philadelphia. I'm a member of the Jefferson Comprehensive Epilepsy Center and also serve as the vice chair of clinical affairs for the department.  Dr Berkowitz: Thank you very much for joining us and for this fantastic article. It's very comprehensive, detailed, a very helpful review of the various types of brain pathology that can lead to epilepsy with very helpful images and descriptions of some of the more common findings like mesial temporal sclerosis and some of the less common ones such as cortical malformations, heterotopia, ganglioglioma, DNET. So, I encourage all of our listeners to read your article and take a close look at those images. So, hopefully you can recognize some of these findings on patients' neuroimaging studies, or if you're studying for the right or the boards, you can recognize some of these less common congenital malformations that can present in childhood or adulthood with epilepsy. In our interview today, what I'd like to do is focus on some practical tips to approaching, ordering, and reviewing different neuroimaging studies in patients with epilepsy. So to start, what's your approach when you're reviewing an MRI for a patient with a first seizure or epilepsy? What sequence do you begin with and why, how do you proceed through the different sequences and planes? What exactly are you looking for?  Dr Skidmore: It's an important question. And I think to even take a step back, I think it's really important, when we're ordering the MRI, we really need to be specific and make sure that we're mentioning the words seizures and epilepsy because many radiology centers and many medical centers have different imaging protocols for seizure and epilepsy patients as compared to, like, a stroke patient or a brain tumor patient. I think first off, we really need to make sure that's in the order, so that way the radiologist can properly protocol it. Once I get an image, though, I treat an MRI just like I would a CAT scan approach with any patient, which is to always approach it in the same fashion. So, top down, if I'm looking at an axial image. If I'm looking at a coronal image, I might start at the front of the head and go to the back of the head. And I think taking that very organized approach and looking at the whole brain in total first and looking across the flare image, a T2-weighted image and a T1-weighted image in those different planes, I think it's important to look for as many lesions as you can find. And then using your clinical history. I mean, that's the value of being a neurologist, is that we have the clinical history, we have the neurological exam, we have the history of the seizure semiology that can might tell us, hey, this might be a temporal lobe seizure or hey, I'm thinking about a frontal lobe abnormality. And then that's the advantage that we often have over the radiologist that we can then take that history, that exam, and apply it to the imaging study that we're looking at and then really focus in on those areas. But I think it's important, and as I've illustrated in a few of the cases in the chapter, is that don't just focus on that one spot. You really still need to look at the whole brain to see if there's any other abnormalities as well. Dr Berkowitz: Great, that's a very helpful approach. Lots of pearls there for how to look at the imaging in different planes with different sequences, comparing different structures to each other. Correspondent reminder, listeners, to look at your paper. That's certainly a case where a picture is worth a thousand words, isn't it, where we can describe these. But looking at some of the examples in your paper, I think, will be very helpful as well. So, you mentioned mentioning to the neuroradiologist that we're looking for a cause of seizures or epilepsy and epilepsy protocols or MRI. What is sort of the nature of those protocols if there's not a quote unquote “ready-made” one at someone 's center in their practice or in their local MRI center? What types of things can be communicated to the radiologist as far as particular sequences or types of images that are helpful in this scenario? Dr Skidmore: I spent a fair amount of time in the article going over the specific MRI protocol that was designed by the International League Against Epilepsy. But what I look for in an epilepsy protocol is a high-resolution T2 coronal, a T2 flare weighted image that really traverses the entire temporal lobe from the temporal tip all the way back to the most posterior aspects of the temporal lobe, kind of extending into the occipital lobe a little bit. I also want to see a high resolution. In our center, it's usually a T1 coronal image that images the entire brain with a very, very thin slice, and usually around two millimeters with no gaps. As many of our neurology colleagues are aware, when you get a standard MRI of the brain for a stroke or a brain tumor, you're going to have a relatively thick slice, anywhere from five to eight millimeters, and you're actually typically going to have a gap that's about comparable, five to eight millimeters. That works well for large lesions, strokes, and big brain tumors, but for some of the tiny lesions that we're talking about that can cause intractable epilepsy, you can have a focal cortical dysplasia that's literally eight- under eight millimeters in size. And so, making sure you have that nice T1-weighted image, very thin slices with no gaps, I think is critical to make sure we don't miss these more subtle abnormalities. Dr Berkowitz: Some of the entities you describe in your paper may be subtle and more familiar to pediatric neurologists or specialized pediatric neuroradiologists. It may be more challenging for adult neurologists and adult neuradiologists to recognize, such as some of the various congenital brain malformations that you mentioned. What's your approach to looking for these? Which sequences do you focus on, which planes? How do you use the patient 's clinical history and EEG findings to guide your review of the imaging? Dr Skidmore: It's very important, and the reason we're always looking for a lesion---especially in patients that we're thinking about epilepsy surgery---is because we know if there is a lesion, it increases the likelihood that epilepsy surgery is going to be successful. The approach is basically, as I mentioned a little bit before, is take all the information you have available to you. Is the seizure semiology, is it a hyper motor semiology or hyperkinetic semiology suggestive of frontal lobe epilepsy? Or is it a classic abdominal rising aura with automatisms, whether they be manual or oral automatisms, suggesting mesial temporal lobe epilepsy? And so, take that clinical history that you have to help start to hone your eye into those individual locations. But then, once you're kind of looking in these nonlesional cases, you're also then looking at the EEG and where their temporal lobe spikes, where their frontal lobe spikes, you know, using that and pulling that information in. If they saw a neuropsychologist pulling in the information in from the neuropsychological evaluation; if they have severe reductions in verbal memory, you know, focusing on the dominant temporal lobe. So, in a right-handed individual, typically the left temporal lobe. And kind of then really spending a lot of time going slice at a time, very slowly, because in some of these vocal-cortical dysplasias it can be just the blurring of the gray-white margin. What I find easiest is to identify that gray-white margin and almost track it. Like, you use the mouse to kind of track it around and say, can I outline the exact border of the gray white margin in the frontal lobe that I'm interested in or the temporal lobe that I'm interested in, kind of looking for those subtle abnormalities. Often as neurologists, we don't have the luxury of being able to immediately reformat. As I mentioned, our T1 volume acquisition study is done in the coronal plane, but sometimes you might want it in the axial plane. And so, I might reach out to the radiologist and say, hey, can you reformat this in the axial plane because I'm interested in the frontal lobe epilepsy and it's a little bit better at looking at it in that plane? And I'll have them reformat and put it back on the pack so I can look at it in that manner. And so that's a, kind of another strategy is to take what you have, but also then go back to the radiologist and say, I need to look at it this a different way. Can you reformat it for me? Looking for that gray-white matter junction is the nice way to pick up for kind of subtle cortical dysplasias. And then when you see an abnormality, to be able to put the T1, the T2, and the flare image all up next to each other and use the technology built into most of our browsers to put on what's called the localizer mode, where I can highlight a specific spot that I'm seeing on the T1 and then very easily quickly see, what does it look like on the T2? What does it look like on the flare? To kind of quickly decide, is it a true abnormality or am I only seeing it on one slice because of an artifact on that one imaging sequence? And I think that's the biggest kind of key is to make sure, is it an artifact or is it not an artifact? That's kind of the most common thing that we, I think, get confused with.  Dr Berkowitz: So, some very helpful pearls there in terms of reviewing the imaging, being in dialogue with our neuroradiology colleagues to think about potentially reacquiring certain images on certain planes or looking at the images with our neuroradiology colleagues to let them know more about the clinical history and where we're sort of zooming in about possible abnormalities.  Dr Skidmore: I would just add in there that when looking at especially the mesial temporal structures, because of a lot of artifacts that can be present in an individual MRI machine, it's not uncommon that the mesial temporal structure will appear brighter because of an MRI magnet artifact. And so, it's a good key to look at the hippocampus compared to the insula. And so, the hippocampus and the insula should have similar signal characteristics. You're seeing the hippocampus is bright, but the insula  ipsilateral to it's normal intensity. That would suggest that that's probably a true hyperintensity on the flare-weighted image as opposed to if both are bright, unless you're suspecting a hemispheric abnormality, it's more likely to be a kind of artifact in the MRI machine. Dr Berkowitz: Okay. Those are really helpful tips, not just to analyze the hippocampus and medial temporal lobe itself---let's remember our anatomy and the circuit of Papez---and to look at associated structures for supporting evidence of a possible abnormality in the hippocampus itself. It looks like there may be something subtle. We can use some additional information from the image to try to decide if that is real or artifactual, and of course correlating with the clinical picture and EEG. I'd like to talk briefly now about some other imaging modalities that you discuss in your paper, the use of functional imaging such as PET, SPECT and fMRI. Let's talk a bit about each of these. When would you order a PET scan for a patient with epilepsy? What would you be looking for and how would you be using that to make clinical decisions?  Dr Skidmore: Yeah, so these functional imaging modalities are really utilized when we're evaluating somebody that's not responding to medications. So, they're medically intractable, and we're wondering, could they be a candidate for epilepsy surgery? And so, most of these imaging modalities are really relegated to the world of epileptologists at surgical epilepsy centers. I wanted to include them, though, in the article because I do think it's important for general neurologists to understand kind of what they are, because invariably a patient sees me and then they go back to their general neurology and be like, hey, Doctor Skidmore said I had this PET scan abnormality. What do you think? So, I think it's a good idea for general neurologists to kind of understand them. So, probably the oldest that we've utilized is the FDG PET scan, basically looking at fluorodeoxyglucose and the brain's utilization of glucose. As we all remember, again, glucose is the primary molecule for energy and ATP production in the brain. And so basically, by injecting radioactive glucose in the interictal state--- so not during a seizure but in between seizures---areas of the brain that are not taking up the radiotracer will show as being hypometabolic. So, low metabolism. And hypometabolic regions in the interictal state have been associated with onset regions for epileptic seizures. Let's say you have a patient clinical history, you think they have temporal of epilepsy, EEG suggests temporal of epilepsy, but the MRI is nonlesional, meaning there's no abnormality that anybody could appreciate even at a 3 Tesla scanner. We'll get an FDG PET scan and see, is there hypo metabolism in that temporal lobe of interest? And if there is, well, that's been shown through several published papers, that's just as valuable as having an abnormality on the MRI. And so, we often again use these PET scans, especially in nonlesional cases, to try to find that subtle cortical dysplasia. Now you have your nice epilepsy protocol MRI, it says it's nonlesional. You get your PET scan, it shows hypometabolism in a region of the frontal lobe, let's say, in a in a frontal lobe epilepsy case. And then often we go back, we kind of talked about strategy of how you find those subtle lesions. Then you go back and say, well, look, this gyrus specifically on the PET scan said it's abnormal. You end up looking for really subtle, very tiny abnormalities that, even with somebody that's skilled, often at first review gets missed. So, that's how we use the PET scan. The SPECT scan is done typically in the ictal state. So, now somebody's in an epilepsy monitoring unit often, where you're injecting radio tracer at the exact moment that somebody starts having a seizure. And we know when there's increased seizure activity, the increased seizure activity---let's say it's from my right temporal lobe---is going to increase cerebral blood flow transiently to the right temporal lobe. And then if that seizure discharge spreads from the right temporal lobe maybe to the entire right hemisphere and eventually becomes a focal to bilateral tonic chronic seizure by spreading to the other side, the entire brain is going to be hypoperfused at that point. So, if you want to, as soon as the seizure starts, inject that radio tracer to see, where is the blood flow earliest in the seizure? And then we might do an interictal SPECT when you're not having a seizure. Look at, all right, what's the normal blood flow when somebody's not seizing? What's it like when they're having a seizure? And then the area that has increased activity would- might suggest that's where the seizure started from. But we have to be very careful because again, some seizures can spread very rapidly. So, if you delay injecting an injection ten, fifteen, twenty seconds, the seizure could have already propagated to another region of the brain, giving you a false positive in another location. So, you have to be very careful about that modality. I think what's most exciting is the functional MRI because the functional MRI, for many, many centers, is replacing a very old technique called the WADA test. So, in the WADA test, typically you place a catheter angiogram into the internal carotid artery and transiently introduce a sedative medication to put, let's say, the left hemisphere to sleep because you wanted to see what functions were still active in the right hemisphere. And then the surgeon would move the catheter or the right internal carotid artery, and you inject a sedative on that side after the left hemisphere is recovered and see what the left hemisphere can do. And we used that for language dominance, we used that for memory dominance. And while most individuals did fine with angiograms, unfortunately complications do occur and there's injury to the artery, there could be strokes that can- that have happened, which can be quite devastating for the patient. And so, functional MRI is a nice, noninvasive way for us to map out language function, motor function, sensory function, visual function, and is starting to show some usefulness also for mapping out kind of memory function, dominant memory function, meaning verbal memory compared to visual memory. To be able to do those things noninvasively becomes really important because, if we're talking about epilepsy surgery, we want to make you seizure-free but neurologically intact. And so, we need to understand the relationship between where we think the seizures are coming from and where eloquent cortex is so we can properly counsel you and avoid those regions during any planned surgery. Those are the three most common functional imaging modalities that we're using now to supplement the rest of the presurgical work.  Dr Berkowitz: Very helpful. So, these are studies, PET, SPECT, and fMRI, that would really be obtained predominantly in patients in whom epilepsy surgery was being considered to have more precise lesion localization, as well as with the fMRI to get a better sense of how to provide the safest maximal resection of epileptogenic tissue while preserving functions. Dr Skidmore: That's a perfect summary.  Dr Berkowitz: Fantastic. This has been a really helpful interview with Dr Skidmore and a really fantastic article. As I said, a picture is worth a thousand words, so I definitely encourage you to read the article and look at the images of some of the conditions we've been talking about and some of these findings that can be seen on interictal PET or ictal SPECT to get a sense of the visual aspects of what we've been discussing. So again, today I've been interviewing Dr Christopher Skidmore about his article on neuroimaging and epilepsy, which appears in the most recent issue of Continuum on Epilepsy. Be sure to check out Continuum audio episodes from this and other issues. And thank you so much to our listeners for joining us today.  Dr Skidmore: Thank you for having me. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Dr. Stéphanie Gaillard and Dr. Bill Tew share updates to the evidence-based guideline on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer. They highlight recommendations across ten clinical questions, addressing initial assessment, primary cytoreductive surgery, neoadjuvant chemotherapy (NACT), tests and/or procedures that should be completed before NACT, preferred chemotherapy regimens, timing of interval cytoreductive surgery (ICS), hyperthermic intraperitoneal chemotherapy (HIPEC), post ICS-chemotherapy, maintenance therapy, and options for those without a clinical response to NACT. They highlight the evidence supporting these recommendations and emphasize the importance of this guideline for clinicians and patients. Read the full guideline update, “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update” at www.asco.org/gynecologic-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Stéphanie Gaillard from Johns Hopkins University and Dr. Bill Tew from Memorial Sloan Kettering Cancer Center, co-chairs on “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Gaillard and Dr. Tew. Dr. Bill Tew: Thank you for having us. Dr. Stéphanie Gaillard: Yeah, thank you. It's great to be here. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gaillard and Dr. Tew, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, Dr. Tew, could you describe what prompted this update to the neoadjuvant chemotherapy for ovarian cancer guideline? And what is the scope of this update? Dr. Bill Tew: Yeah. It's been almost a decade since ASCO first published its neoadjuvant chemotherapy guidelines for women with newly diagnosed ovarian cancer, and over that 10-year period, there's really been a major shift in how oncologists treat patients in the U.S. If you look at the National Cancer Database, between 2010 and 2021, the proportion of patients with advanced ovarian cancer who underwent primary surgery fell from about 70% to about 37%. And there's been a doubling in the amount of neoadjuvant chemotherapy used. So we wanted to take a look at that and really both highlight the appropriate patient populations for primary surgery versus new adjuvant chemotherapy, as well as review any studies that have been published since then. There's been, I think, about 61 trials published, nine randomized trials alone in the last 10 years. And the scope of the guideline was really not only the neoadjuvant chemotherapy and surgical questions, but also to touch upon some new treatments that have come to the forefront in newly diagnosed ovarian cancer, including heated intraperitoneal chemotherapy or HIPEC, as well as the integration of maintenance therapy, particularly bevacizumab and PARP inhibitors. Brittany Harvey: Understood. That's a large amount of new evidence to review in this Update. Then, next, Dr. Gaillard, I'd like to review the key recommendations across the 10 clinical questions that the guideline addressed. So, starting with: What is recommended regarding initial assessment for patients with newly diagnosed pelvic masses and/or upper abdominal or peritoneal disease? Dr. Stéphanie Gaillard: Sure. So in talking about the first guidelines, the first one that we addressed was how to do the initial assessment for these patients. And first, and probably most critically, it's important to recognize that these patients really should be evaluated by a gynecologic oncologist prior to initiation of any therapy, whether that means a primary cytoreductive surgery or neoadjuvant chemotherapy, because really, they are the best ones to determine the pathway that the patient should take. The initial assessment should involve a CA-125, a CT of the abdomen and pelvis with oral and IV contrast, if not contraindicated, and then also chest imaging, in which a CT is really the preferred modality. And that helps to evaluate the extent of disease and the feasibility of the surgical resection. Now, there may be some other tools that could be helpful to also refine this assessment. So, for example, a laparoscopy can really help to determine the feasibility of surgical resection as well as the extent of disease. Further imaging, such as diffusion-weighted MRI or FDG-PET scans can be helpful, as well as ultrasounds. And then also an endometrial biopsy. And that was newly added because there really has been a divergence of treatment for endometrial cancer versus ovarian cancer. And so it's really important to determine upfront where the source of the disease is coming from. Brittany Harvey: I appreciate you describing those recommendations surrounding initial assessment. So following this assessment, Dr. Tew, which patients with newly diagnosed advanced epithelial ovarian cancer should be recommended primary cytoreductive surgery? Dr. Bill Tew: The key thing here is if the GYN oncology surgeon feels that they have a high likelihood of achieving a complete cytoreduction with acceptable morbidity, the panel overwhelmingly agrees that primary cytoreduction surgery should be recommended over chemotherapy. And we know that surgery is really the cornerstone to achieving clinical remission. And our concern is that neoadjuvant chemotherapy may be overused in this fit population. Sometimes it is challenging to determine truly if a patient has a high likelihood of complete cytoreduction or what is acceptable morbidity. But an evaluation with performance status, fitness, looking at age or frailty, nutritional status, as well as a review of imaging studies to plan and determine for who is the right patient for primary surgery is key. Brittany Harvey: And then the title of this guideline, Dr. Gaillard, for which patients is neoadjuvant chemotherapy recommended? Dr. Stéphanie Gaillard: Yeah. So there's really two patient populations that we think are best suited to receive neoadjuvant chemotherapy. Those may be patients who are fit for a primary cytoreductive surgery, but they're unlikely to have a complete cytoreduction if they were to go to surgery directly. And so that's where neoadjuvant chemotherapy can be very helpful in terms of increasing the ability to obtain a complete cytoreduction. The second population is those who are newly diagnosed who have a high perioperative risk, and so they're not fit to go to surgery directly. And so it may be better to start with neoadjuvant chemotherapy and then do an interval cytoreductive surgery. Again, I just want to emphasize the importance of including a gynecologic oncologist when making these determinations for patients. Brittany Harvey: Absolutely. So then the next clinical question. Dr. Tew, for those patients with newly diagnosed stage 3 to 4 epithelial ovarian cancer, what tests and or procedures are recommended before neoadjuvant chemotherapy is delivered? Dr. Bill Tew: The key test is to confirm the proper diagnosis, and that requires histological confirmation with a core biopsy. And this was a point the panel strongly emphasized, which is a core biopsy is a much better diagnostic tool compared to cytology alone. But there will be cases, exceptional cases, where a core biopsy cannot be performed. And in those settings, cytology combined with serum CA-125 and CEA is acceptable to exclude a non-gynecologic cancer. The other reason why cord biopsy is strongly preferred is because we already need to start thinking about germline and somatic testing for BRCA1 and 2. This information is important as we start to think about maintenance strategies for our patients. And so having that information early can help tailor the first-line chemotherapy regimen. Brittany Harvey: So then you've described who should be receiving neoadjuvant chemotherapy, but Dr. Gaillard, for those who are receiving neoadjuvant chemo, what is the preferred chemotherapy regimen? And then what does the expert panel recommend regarding timing of interval cytoreductive surgery? Dr. Stéphanie Gaillard: Sure. So for neoadjuvant chemotherapy, we generally recommend a platinum taxane doublet. This is especially important for patients with high grade serous or endometrioid ovarian cancers, and that's really because this is what the studies had used in the neoadjuvant trials. We recognize, however, that sometimes there are individual patient factors, such as advanced age or frailty, or certain disease factors such as the stage or rare histology that may shift what is used in terms of chemotherapy, but the recommendation is to try to stick as much as possible to the platinum taxane doublet. And then in terms of the timing of interval cytoreductive surgery, this was something that the panel discussed quite a bit and really felt that it should be performed after four or fewer cycles of neoadjuvant chemotherapy, especially in patients who've had a response to chemotherapy or stable disease. Sometimes alternative timing of surgery can be considered based on some patient centered factors, but those really haven't been prospectively evaluated. The studies that looked at neoadjuvant chemotherapy usually did the interval cytoreductive surgery after three or four cycles of chemotherapy. Brittany Harvey: For those patients who are receiving interval cytoreductive surgery, Dr. Tew, earlier in the podcast episode, you mentioned a new therapy. What is recommended regarding hyperthermic intraperitoneal chemotherapy? Dr. Bill Tew: Yeah, or simply HIPEC as everyone refers to it. You know, HIPEC isn't really a new therapy. HIPEC is a one-time perfusion of cisplatin, which is a chemotherapy that has been a standard treatment for ovarian cancer for decades. But the chemotherapy is heated and used as a wash during the interval cytoreductive surgery. And since our last guideline, there has been a publication of a randomized trial that looked at the use of HIPEC in this setting. And in that study there was improved disease-free and overall survival among the patients that underwent HIPEC versus those that did not. So we wanted to at least emphasize this data. But we also wanted to recognize that HIPEC may not be available at all sites. It's resource-intensive. It requires a patient to be medically fit for it, particularly renal function and performance status. And so it's something that could be discussed with the patient as an option in the interval cytoreductive surgery. One other point, the use of HIPEC during primary surgery or later lines of therapy still is unknown. And the other point is this HIPEC trial came prior to the introduction of maintenance PARP inhibitors. So there's still a lot of unknowns, but it is a reasonable option to discuss with appropriate patients. Brittany Harvey: I appreciate you reviewing that data and what that updated recommendation is from the panel. So then, Dr. Gaillard, after patients have received neoadjuvant chemotherapy and interval cytoreductive surgery, what is the post ICS chemotherapy recommended? Dr. Stéphanie Gaillard: The panel recommends some post ICS chemotherapy, as you mentioned. This is typically to continue the same chemotherapy that was done as neoadjuvant chemotherapy and so preferably platinum and taxane. And typically we recommend a total of six cycles of treatment, although the exact number of cycles that is given post-surgery can be adjusted based on different patient factors and their response to treatment. Importantly, also, timing is a factor, and we recommend that postoperative chemotherapy begin within four to six weeks after surgery, if at all feasible. Brittany Harvey: Absolutely. Those timing recommendations are key as well. So then, Dr. Tew, you mentioned this briefly earlier, but what is the role of maintenance therapy? Dr. Bill Tew: Maintenance therapy could be a full podcast plus of discussion, and it's complicated, but we did want to include it in this guideline in part because the determination of whether to continue treatment after completion of surgery and platinum based therapy is key as one is delivering care in the upfront setting. So first off, when we say maintenance therapy, we are typically referring to PARP inhibitors or bevacizumab. And I would refer listeners to the “ASCO PARP Inhibitor Guideline” that was updated about two years ago, as well as look at the FDA-approved label indications. But in general, PARP inhibitors, whether it's olaparib or niraparib, single agent or olaparib with bevacizumab, are standard treatments as maintenance, particularly in those patients with a germline or somatic BRCA mutation or those with an HRD score positive. And so it's really important that we emphasize germline and somatic BRCA testing for all patients with newly diagnosed ovarian cancer so that one can prepare for the use of maintenance therapy or not. And the other point is, as far as bevacizumab, bevacizumab is typically initiated during the chemotherapy section of first-line treatment. And in the guidelines we gave specific recommendations as far as when to start bevacizumab and in what patient population. Brittany Harvey: Great. Yes. And the PARP inhibitors guideline you mentioned is available on the ASCO guidelines website and we can provide a link in the show notes for our listeners. So then, the last clinical question, Dr. Gaillard, what treatment options are available for patients without a clinical response to neoadjuvant chemotherapy? Dr. Stéphanie Gaillard: Yeah, this is a tough situation. And so it's important to remember that ovarian cancer typically does respond to chemotherapy initially. And so it's unusual to have progressive disease to neoadjuvant chemotherapy. So it's really important that if someone has progressive disease that we question whether we really have the right diagnosis. And so it's important to, I think at that point, obtain another biopsy and make sure that we know what we're really dealing with. In addition, this is where Dr. Tew mentioned getting the molecular profiling and genetic testing early in the course of disease. If that hasn't been done at this point in time, it's worth doing that in this setting so that that can also potentially help guide options for patients. And patients who are in those situations, really, the options are other chemotherapy regimens, clinical trials may be an option, or in some situations, if they have really rapidly progressing disease that isn't amenable to further therapy, then initiation of end-of-life care would be appropriate. Brittany Harvey: I appreciate you both for reviewing all of these recommendations and options for patients with advanced ovarian cancer. So then to wrap us up, in your view, what is both the importance of this guideline update and how will it impact clinicians and patients with advanced ovarian cancer? Dr. Bill Tew: Well, first off, I'm very proud of this guideline and the panel that I work with and Dr. Gaillard, my co-chair. The guideline really pulls together nicely all the evidence in a simple format for oncologists to generate a plan and determine what's the best step for patients. The treatment of ovarian cancer, newly diagnosed, is really a team approach - surgeons, medical oncologists, and sometimes even general gynecologists - and understanding the data is key, as well as the advances in maintenance therapy and HIPEC. Dr. Stéphanie Gaillard: For my part, I'd say we hope that the update really provides physicians with best practice recommendations as they navigate neoadjuvant chemotherapy decisions for their patients who are newly diagnosed with ovarian cancer. There is a lot of data out there and so we hope that we've synthesized it in a way that makes it easier to digest. And along that regard, I really wanted to give a special shout out to Christina Lacchetti, who just put in a tremendous effort in putting these guidelines together and in helping to coordinate the panel. And so we really owe a lot to her in this effort. Dr. Bill Tew: Indeed. And ASCO, as always, helps guide and build a great resource for the oncology community. Brittany Harvey: Absolutely. Yes, we hope this is a useful tool for clinicians. And I want to thank you both for the large amount of work you put in to update this evidence-based guideline. And thank you for your time today, Dr. Gaillard and Dr. Tew. Dr. Stéphanie Gaillard: Thank you. Dr. Bill Tew: Thank you for having us. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   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.  

A pragmatic and organized approach is needed to recognize patients with symptomatic Alzheimer Disease in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making. In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Gregory S. Day, MD, MSc, MSCI, FAAN, author of the article “Diagnosing Alzheimer Disease,” in the Continuum December 2024 Dementia issue. Dr. Berkowitz is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Day is an associate professor in the Department of Neurology at Mayo Clinic Florida in Jacksonville, Florida. Additional Resources Read the article: Diagnosing Alzheimer Disease Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @GDay_Neuro Full episode transcript available here Dr Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I have the pleasure of interviewing Dr Gregory Day about his article on Alzheimer disease, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Day. Would you mind introducing yourself to our audience?  Dr Day: Thanks very much, Aaron. I'm Gregg Day. I'm a behavioral neurologist at Mayo Clinic in Jacksonville, Florida, which means that my primary clinical focus is in the assessment of patients presenting typically with memory concerns and dementia in particular. Dr Berkowitz: Fantastic. Well, as we were talking about before the interview, I've heard your voice many times over the Neurology podcast and Continuum podcast. I've always learned a lot from you in this rapidly changing field over the past couple of years, and very excited to have the opportunity to talk to you today and pick your brain a little bit on this very common issue of evaluating patients presenting with memory loss who may have concerns that they have dementia and specifically Alzheimer disease. So, in your article, you provide a comprehensive and practical approach to a patient presenting for evaluation for possible dementia and the question of whether they have Alzheimer disease. The article is really packed with clinical pearls, practical advice. I encourage all of our listeners to read it. In our interview today, I'd like to talk through a theoretical clinical encounter and evaluation so that I and our listeners can learn from your approach to a patient like this. Let's say we have a theoretical patient in their seventies who comes in for evaluation of memory loss and they and/or their family are concerned that this could be Alzheimer disease. How do you approach the history in a patient like that? Dr Day: It's a great way to approach this problem. And if you're reading the article, know that I wrote it really with this question in mind. What would I be doing, what do we typically do, when we're seeing patients coming with new complaints that concern the patient and typically also concern those that know the best? So be that a family member, close friend, adult child. And in your scenario here, this seventy year old individual, we're going to use all the information that we have on hand. First off, really key, if we can, we want to start that visit with someone else in the room. I often say when talking to individuals who come alone that there's a little bit of irony in somebody coming to a memory assessment alone to tell me all the things they forgot. Some patients get the joke, others not so much, but bringing someone with them really enhances the quality of the interview. Very important for us to get reliable information and a collateral source is going to provide that in most scenarios. The other thing that I'm going to start with, I'm going to make sure that I have appropriate time to address this question. We've all had that experience. We're wrapping up a clinical interview, maybe one that's already ran a little bit late and there's that one more thing that's mentioned on the way out the door: I'm really concerned about my memory or I'm concerned about mom 's memory. That's not the opportunity to begin a memory assessment. That's the opportunity to schedule a dedicated visit. So, assuming that we've got someone else in the room with us, we've got our patient of interest, I'm going to approach the history really at the beginning. Seems like an easy thing to say, but so often patients in the room and their caregivers, they've been waiting for this appointment for weeks or months. They want to get it out all out on the table. They're worried we're going to rush them through and not take time to piece it together. And so, they're going to tell you what's going on right now. But the secret to a memory assessment, and particularly getting and arriving at an accurate diagnosis that reflects on and thinks about cause of memory problems, is actually knowing how symptoms began. And so, the usual opening statement for me is going to be: Tell me why you're here, and tell me about the first time or the first symptoms that indicated there was an ongoing problem. And so, going back to the beginning can be very helpful. This article is focused on Alzheimer disease and our clinical approach to the diagnosis of Alzheimer disease. And so, what I'm going to expect in a patient who has a typical presentation of Alzheimer disease is that there may be some disagreement between the patient and the spouse or other partners sitting in the room with me about when symptoms began. If you've got two partners sitting in the room, maybe an adult child and a spouse, there may be disagreement between them. What that tells me is at the onset, those first symptoms, they're hard to pin down. Symptoms typically emerge gradually in patients with symptomatic Alzheimer disease. They may be missed early on, or attributed or contributed to other things going on in the patient's time of life, phase of life. It's okay to let them sort of duke it out a little bit to determine, but really what I'm figuring out here is, are we talking about something that's happened across weeks, months or more likely years? And then I'm going to want to listen to, how did symptoms evolve? What's been the change over time? With Alzheimer disease and most neurodegenerative diseases, we expect gradual onset and gradual progression, things becoming more apparent. And at some point, everyone in the room is going to agree that, well, as of this state, there clearly was a problem. And then we can get into talking about specific symptoms and really begin to pick that apart the way that we traditionally do in any standard neurological assessment. Dr Berkowitz: Fantastic. And so, what are some of the things you're listening for in that history that would clue you in to thinking this patient may indeed be someone who could have Alzheimer's disease and going to require a workup for that diagnosis? Dr Day: It's pretty common when I have new trainees that come to clinic, they just head into the exam room and they sort of try to approach it the way that we would any patient in the emergency department or any other clinical scenario. The challenge with that is that, you know, we're taught to let the patient speak and we're going to let the patient speak - open-ended questions are great - but there's only so many questions you need to sort out if someone has a memory problem. And memory is really only one part, one component, of a thorough cognitive evaluation. And so, I'm going to help by asking specific questions about memory. I'm going to make sure that there is memory challenges there. And whenever possible, I'm going to solicit some examples to back that up, add credibility and sort of structure to the deficits. I'm also going to choose examples that help me to understand how does this concern, or this complaint, how does that actually affect the patient in their day-to-day life? Is it simply something that they're aware of but yet hasn't manifested in a way that their partner knows about? Is it to a level where their partner's actually had to take over their responsibility? It's causing some difficulties, disability even, associated with that. That's going to be important for me as I try to understand that. So, I'll ask questions when it comes to memory, not just, you know, do you forget things, but do you manage your own medications? You remember to take those in the morning? Do you need reminders from your partner? What about appointments; health appointments, social appointments? Are you managing that on your own? Sometimes we need a little bit of imagination here. Partnerships, and particularly those who have been together for a long time, it's natural that different people are going to assume different responsibilities. And so, might have to say, Imagine that you went away for the weekend. Would you worry about your partner remembering to take their medications over that time frame? That can help to really solidify how much of an impact are these challenges having on a day-to-day basis. I may ask questions about events, something that they maybe did a couple of weeks ago. Is the patient likely to remember that event? Are they going to forget details? Maybe the most important of all, with each of these, when there's a yes or an affirmation of a problem, we want to be clear that this represents a change from before. We all have forgetfulness. Happens on a day-to-day basis, and we all pay attention to different details, but what we're concerned about and typically the reasons patients want to come and see us as neurologists is because they've noticed a change. And so, I'm going to focus in on the things that represent a change from before. After I've discussed memory, I think it's really important to talk about the other domains. So, how is judgment affected? Decision-making?  In a practical way, we often see that borne out in financial management, paying the bills. Not just paying them on time and consistently, but making wise choices when it comes to decisions that need to be made. You're out at a restaurant. Can you pay the bill? Can you calculate a tip? Can you do that as quickly and as efficiently as before? Are we starting to see a breakdown in decision-making abilities there? We can sometimes lump in changes in behavior along with judgment as well. The patient that you know, maybe isn't making wise choices, they've picked up the phone and given their social security number out to someone that was calling, seeming to be well-meaning. Or maybe they've made donations to a few more institutions than they would have otherwise? Again, out of- out of order. Again, something that could be atypical for any individual. Looking for behavioral changes along with that as well. And then I'm going to talk about orientation. What's their ability to recognize days of the week, date of the month? Do they get lost? Is there concerns about wayfinding? Thinking about that, which is really a complex integration of some memory, visuospatial processing, judgment, problem solving, as we look to navigate our complex world and find our way from point A to B. And then I like to know, you know, what are they doing outside of the home? What are they doing in the community? How are they maintaining their engagement? Do they go to the store? Do they drive? An important topic that we may need to think about later on in this patient 's assessment. And inside the home? What responsibilities do they maintain there? Are the changes in decision making, memory problems, are they manifesting in any lost abilities inside the home? Cooking being a potentially high-risk activity, but also using typical appliances and interacting with technology, in a way that we are all increasingly, increasingly doing and increasingly reliant on. And last but not least, you know, maybe the one that everyone wants to think about, well, I can still manage all of my own personal care. Well, good news that many of our patients who have early symptoms can manage their own personal care. Their activities of daily living are not the big problem. But we do want to ask about that specifically. And it's not just about getting in the shower, getting clean, getting out, getting your teeth brushed. Do you need reminders to do that? Do you hop in the shower twice because you forgot that you'd already been in there once during the day? And so, asking some more of those probing questions there can give us a little bit more depth to the interview and really does sort of round out the overall comprehensive history taking in a patient with a memory or cognitive concern. Dr Berkowitz: Fantastic. That was a comprehensive master class on how to both sort of ask the general questions, have you noticed problems in fill in the blank memory, judgment, behavior, orientation, navigation and to sort of drill down on what might be specific examples if they're not offered by the patient or partner to try to say, well, in this domain, tell me how this is going or have you noticed any changes because the everyone's starting from a different level cognitively based on many factors. Right? So, to get a sense of really what the change is in any of these functions and how those have impacted the patient's daily life. So, let's say based on the history, the comprehensive history you've just discussed with us, you do find a number of concerning features in the history that do raise concern for dementia, specifically Alzheimer's disease. How do you approach the examination? We have the MoCA, the mini-mental. We have all of these tools that we use. How do you decide the best way to evaluate based on your history to try to get some objective measure to go along with the more subjective aspects of the history that you've ascertained? Dr Day: And you're honing in on a really good point here, that the history is one part of the interview or the assessment. We really want to build a story and potentially and hopefully a consistent story. If there are memory complaints, cognitive complaints from history, from reliable- that are supported by reliable collateral sources, we're going to expect to see deficits on tests that measure those same things. And so, I think that question about what neuropsychological measures or particular bedside tests can we integrate in our assessment is a good one. But I'll say that it's not the end-all-be-all. And so, if you've got a spouse, someone that lives with an individual for twenty or thirty years, and they're telling you that they notice a change in daily activity and it's impairing their day to day function, or where there's been some change or some concern at work, that's going to worry me more than a low score on a cognitive test with a spouse saying they haven't noticed any day-to-day impact. And so, we're going to take everything sort of in concert and take it all together. And it's part of our job as clinicians to try to process that information. But often we're going to see corroborating history that comes from a bedside test. He named a few that our listeners are probably pretty familiar with. I think they're the most common ones that are used. The Mini-Mental State Exam, been in practice for a long time. All the points add up to thirty and seems to give a pretty good sample of various different cognitive functions. The Montreal Cognitive Assessment, another favorite; a little bit more challenging of a test, I think, if we're if we're looking at how people tend to perform on it. And like the MMSE, points add up to thirty and gives a pretty good sample. There are others that are out there as well, some that are available without copyright and easy for use in clinical practice. The Saint Louis Mental Status Exam comes to mind. All these tests that we're willing to consider kind of share that same attribute. They can be done relatively quickly. They should sample various different aspects of function. There should be some component for language reading, spoken, spoken word, naming items, something that's going to involve some kind of executive function or decision making, problem solving. Usually a memory task where you're going to remember a set of words and be asked to recall that again later. So, learn it, encode it, and recall it later on. And then a few other features, I mean, some of them, these tests, most of these tests use some sort of drawing tasks so that we can see visuospatial perception and orientation questions about date, time, location, sort of the standard format. Any of these tests can be used aptly in your practice. You're going to use the one that you're most comfortable with, that you can administer in a reasonable amount of time and that seems to fit with your patient population. And that's the nuance behind these tests. There are many factors that we have to take into account when we're picking one and when we're interpreting the test results. These tests all generally assume that patients have some level of traditional sociocultural education that is westernized for the most part. And so, not great tests for people that aren't well into integrated into the community, maybe newcomers to the United States, those that have English as a second, third, or fourth language, as many of our patients do. Statements like no ifs, ands, or buts may not be familiar to them and may not be as easy to repeat, recall and remember. And so, we want to weigh these considerations. We may need to make some adjustments to the score, but ideally, we're going to use these tests and they're going to show us what we expect and we're going to try to interpret that together with the history that we've already ascertained. When I obtain that history and I'm thinking about memory loss, I'm going to look at the specific domain scores. And so, if I'm using the mini mental state examination thirty point test, but three questions that relate to relate to recall. Apple, penny, table. And so, depending on how our patients do on that test, they could have an overall pretty good score. Twenty seven. Oh, that looks good. You're in the normal range according to many different status. But if I look at that and there's zero out of three on recall, they could not remember those three items, that may support the emergence of a memory problem. That may corroborate that same thing on the MoCA, which uses five-item recall, and other tests in those same parameters. I mentioned some other caveat cities testing. Are patients who are presenting with prominent language deficits important part of cognition. They can't get the words out. They can't frame their sentences. They may really struggle with these tests because a lot of them do require you to both understand verbal instructions and convey verbal instructions. People with prominent visual problems, either visual problems that come because of their neurodegenerative disease and so part of cognition, visual perceptual problems, or people who simply have low vision. Are there difficulties for that? These tests require many people to read and execute motor commands, to draw things, to follow lines and connect dots, all very difficult in that setting. And so, we have to be cautious about how we're interpreting test results in patients who may have some atypical features or may arrive with sort of preexisting conditions that limit our ability to interpret and apply the test to clinical practice.  Dr Berkowitz: Really fantastic overview of these tests, how to use them, how to interpret them. It's not all about the number. As you said, it depends if all the points are lost in one particular domain, that can be salient and then considering, as you said, the patient 's background, their level of education, where English falls in their first language, second, third or fourth, as you said, and then some of the aspects of the MoCA, right, are not always as culturally sensitive since it's a test designed in a particular context. So, let's say your history and exam are now concerning to you, that the patient does indeed have dementia. Tell us a little bit about the next steps in the laboratory neuroimaging evaluation of such a patient?  Dr Day: I've got a history of memory and thinking problems. I've got some corroborating evidence from bedside cognitive testing, a normal neurological exam. This is where we think about, well, what other tests do we need to send our patients for? Blood testing really can be pretty cursory for most patients with a typical presentation who have typical risk factors, and that can include a thyroid study and vitamin B12. So, measuring those in the blood to make sure that there's no other contributions from potential metabolic factors that can worsen, exacerbate cognitive function. And pretty easy to do for the most part, if patients have other things in their history, maybe they come from a high-risk community, maybe they engage in high risk behaviors, I may think about adding on other tests that associate with cognitive decline. We'll think about the role of syphilis, HIV, other infections. But generally, that's when it's driven by history, not a rule of thumb for me in my typical practice. But beyond the blood tests, neuroimaging, some form of structural brain imaging is important. A CT scan will get you by. So, if you have a patient that can't get in the scanner for one reason or another or won't get in the scanner, or you don't have easy access to an MRI, a CT scan can help us in ruling out the biggest things that we're looking for. That's strokes, hemorrhages, and brain masses. So other things that obviously would take us down a very different path, very different diagnosis and very different treatment approach. An MRI, though, is going to be preferred, not only because it gives us a much higher-resolution view, but also because it helps us to see sort of regional areas of atrophy. It's a sensitive scan to look for small vessel disease, tiny strokes, tiny bleeds, microhemorrhages that again might point towards meteorology for us. Of course, it's better at finding those small masses, whether they be metastasis or primary masses, that could give us something else to consider in our diagnostic evaluation. I get an odd question often from patients, well, can you see Alzheimer's disease on an MRI? And the true answer to that is no, you can't. Can we see the signs of Alzheimer's disease? Sure, in some patients, but really what we see on an MRI is a reflection of neurodegeneration. And so, we see evidence of tissue loss and typically in areas that are most often involved early on in Alzheimer's disease. The hippocampus, the entorhinal areas around the hippocampus, we may see atrophy there. We may see biparietal atrophy, and of course, as the disease progresses, we're going to see atrophy distributed throughout other areas of the brain. But if you're looking for atrophy, you've got to have a pretty good idea what's normal for age and what you expect in that patient population. So, I do encourage clinicians who are assessing patients routinely, look at your own images, look at the images for patients with and without cognitive impairment. So we develop a pretty good sense for what can be normal for age, and of course work with our colleagues in radiology who do this for a living and generally do an excellent job at it as well.  Dr Berkowitz: Perfect. So, you're going to look for the so-called reversible causes of dementia with serum labs, structural imaging to either rule out or evaluate for potential structural causes that are not related to a neurodegenerative condition or patterns of regional atrophy suggestive of a neurodegenerative condition, and maybe that will point us in an initial direction. But the field is rapidly expanding with access to FDG-PET, amyloid PET, CSF biomarkers, genetic testing for APOE 4, probably soon to be serum biomarkers. So, patients may ask about this or a general neurologist referring to your clinic may ask, who should get these tests? When should we think about these tests? How do you think about when to send patients for advanced imaging, CSF biomarkers, genetic testing for APOE 4? Dr Day: It's not that patients may ask about this. Patients will ask about this. And you've probably experienced that in your own world as well. They're going to ask about any of these different biomarkers. Certainly, whatever they've recently read or has been covered on television is going to be common fodder for consideration in the clinic environment. It's important to know what tests you can get, what reliable tests that you can get, and to know the differences between some of these tests when making a recommendation or weighing the pros and cons of doing additional testing. I think common practice principles apply here. Let's order tests that are going to change our next steps in some way. And so, if we have a patient, particularly a patient like the one that we've been talking about: seventy something year old, presenting with memory complaints, they're concerned, the family is concerned. We've got that history, physical exam, and now we may need to really hone in on the etiology. Well, I say may need because for that patient it may be enough to know, yeah, I agree, there's a problem here. And I can say it's an amnestic, predominant, gradual-onset progressive cognitive decline. This is probably Alzheimer disease based on your age. And maybe that's all they want to hear. Maybe they're not ready to pursue additional testing or don't see the value or need for additional testing because it's not going to change their perspective on treatment. In that case, it's okay to apply an often underrated test, which is the test of time. Recognizing this is a patient I can follow. I can see them in six months or twelve months, depending on what your clinic schedule allows. If this is Alzheimer disease, I'm going to expect further gradual progression that may affirm the diagnosis. We can think about symptomatic therapies for a patient like that, perhaps Donepezil as an early, early medication that may help with symptoms somewhat and we can leave it at that for the time being. But there's many scenarios where that patient or the family member says, look, I really need to know. We really want this answer. And as you pointed out, there are good tests and increasingly good tests that we have access to.  Dr Berkowitz: Well, that's a very helpful overview of the landscape of more precise diagnostic testing for Alzheimer disease specifically and how you think about which tests to order and when based on your pretest probability and the patient 's candidacy for some of these new potential therapies. To close here, as you said, treatment is discussed in another podcast. There's another article in this issue. So, we won't get into that today. But let's say you have gotten to the end of the diagnostic journey here. You are now convinced the patient does have Alzheimer's disease. How do you present that diagnosis to the patient and their family? Dr Day: I think here we're going to recognize that different styles align with different patients and families, and certainly different clinicians are going to have different approaches. I do tend to take a pretty direct approach. By the time that patients are coming to see me, they've probably already seen another neurologist or at least another physician who's maybe started some of the testing, maybe even built the foundation towards this diagnosis and shared some indications. Certainly, when they look up my profile before they come to see me, they know what I specialize in and so, they may even have done their own research, which has ups and downs in terms of the questions that I'll be faced with at that point in time. The way I like to start is first acknowledging the symptoms. And the symptoms that the patients have shared with me, recognizing if those symptoms are impacting daily life, how they impacted daily life, and usually using that information to synthesize or qualify the diagnosis. Is there cognitive impairment, yes or no? And at what level is that cognitive impairment? Is this mild cognitive impairment? Is this mild dementia? Is it maybe more moderate or severe dementia? So, using those terms directly with patients and explaining the meaning of them. But I then transition in relatively quickly to the important point of not leaving it at the syndrome, but actually thinking about the cause. Because it is cause that patients come to talk about. And if they don't say that directly, they say it in their next question, which is what are we going to do about it and how are we going to treat this? And so, I will use the information I have available at that time to suggest that based on your age, based on the history, the normal physical examination, the performance and the bedside testing that we've done. And hey, that's pretty normal structural imaging or imaging that only shows a little bit of atrophy in a few areas. I think that this condition is most consistent with symptomatic Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease, or mild dementia due to Alzheimer's disease. And then I'll discuss the next options in terms of testing and try to get a feel of what our patients are thinking about when it comes to treatment. Do they want to be on the cutting edge with brand-new therapies that offer potential benefits but counterbalance by pretty substantial risks that warrant individualized discussions? Are they interested in symptomatic therapies? Would that be appropriate for them? And I can usually round out the discussion with advice that works for everyone. And that's where we talk about the importance of brain health. What are the other things that I should be doing, you should be doing, and our patients and their partners should be doing as well to maintain our brain in its best possible state as we hope that we all continue to age and look towards the future where we maintain our cognition as best as possible? And that is still the goal. Even when we're talking to patients who have neurodegenerative diseases that are working against our efforts, we still want to do what we can to treat other problems, to evaluate for other problems that may be contributing to decline and may be amenable to our management as well.  Dr Berkowitz: Well, thank you so much for taking the time to speak with us today. I've learned a lot from your very nuanced and thoughtful approach to taking the history, performing the examination, making sense of cognitive tests and how they fit into the larger picture of the history and examination, and thinking about which patients might be candidates for more advanced imaging as we try to make a precise diagnosis in patients who may be candidates and interested in some of the potential novel therapies, which we both alluded to a few times, but are deferring to another podcast that we'll delve more deeply into that topic in this series. So, thank you so much again, Dr Day. Again, I've been interviewing Dr Gregory Day from the Mayo Clinic, whose article on Alzheimer's disease appears in the most recent issue of Continuum on Dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you so much to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Love the episode? Send us a text!In this episode of Breast Cancer Conversations, we delve into the complexities of living with a metastatic breast cancer diagnosis and explore the various diagnostic and treatment options available. Our panel includes Dr.  Groteluschen, a medical oncologist from Green Bay Oncology, Tammy, a patient living with metastatic breast cancer, and Dr. Covington, a breast radiologist and nuclear radiologist from the University of Utah.Dr. Groteluschen shares his approach to delivering heavy news to patients, emphasizing the importance of honesty, transparency, and hope. He discusses the nuances of different imaging techniques, such as CT scans and PET scans, and how they are used to monitor disease progression and inform treatment decisions. Tammy provides a personal perspective on her journey, highlighting the importance of advocating for oneself and seeking second opinions.Dr. Covington offers insights into the role of radiology in breast cancer care, explaining the differences between FDG PET and FES PET scans. He discusses how these imaging techniques help in identifying the extent and characteristics of the disease, which in turn guides treatment planning.We also touch upon the evolving landscape of breast cancer treatment, including the potential for nuclear medicine-based therapies and the importance of targeted therapy. The episode concludes with reflections from each panelist on what excites them most about the future of breast cancer oncology, from advancements in imaging and targeted therapies to the ongoing development of clinical trials.This episode is a deep dive into the intricacies of metastatic breast cancer, offering valuable insights for patients, caregivers, and healthcare professionals alike.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.https://www.survivingbreastcancer.org/takeahikehttps://www.survivingbreastcancer.org/takeahikeSupport the show

Owen Roberts joins us to explore the dynamic intersection of technology and healthcare, focusing on how innovations like FDG-PET scans and the Human Genome Project have propelled advancements in cancer treatment. The discussion highlights the crucial role of integrating various technological breakthroughs and how Canadian research centres like McMaster are making significant strides in the field. Owen emphasizes the importance of aligning research with clinical needs and the challenges researchers face when transitioning from the lab to the market.

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.

Dr. Iyad Alnahhas interviews Drs. Minyoung Oh and Hyungwoo Cho about their recent manuscript entitled: "Enhancing Prognostication and Treatment Response Evaluation in Primary CNS Lymphoma with 18F-FDG PET/CT", published online in Neuro-Oncology in August 2024.   Link to manuscript

BUFFALO, NY- July 15, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on June 20, 2024, entitled, “Comparison of FDG-PET/CT and CT for evaluation of tumor response to nivolumab plus ipilimumab combination therapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.” Malignant pleural mesothelioma (MPM) is an aggressive neoplasm and affected patients have low survival rates. In this new retrospective study, researchers Kazuhiro Kitajima, Kozo Kuribayashi, Toshiyuki Minami, Hiroyuki Yokoyama, Akifumi Nakamura, Masaki Hashimoto, Takashi Kijima, Seiki Hasegawa, Hayato Kaida, and Koichiro Yamakado from Hyogo Medical University and Kindai University Faculty of Medicine examined the effectiveness of fluorodeoxyglucose positron emission tomography (FDG-PET) criteria, i.e., immunotherapy-modified PET response criteria in solid tumors (imPERCIST), with morphological computed tomography (CT) criteria, i.e., modified response evaluation criteria in solid tumors (mRECIST), to evaluate patients with unresectable MPM undergoing nivolumab plus ipilimumab combination therapy as first-line treatment regarding response and prognosis prediction. “Results for malignant pleural mesothelioma (MPM) patients following first-line treatment with nivolumab plus ipilimumab obtained with immunotherapy-modified PERCIST (imPERCIST), shown by [18F] (FDG-PET/CT), and modified RECIST (mRECIST), shown by CT, were compared for response evaluation and prognosis prediction.” Twenty-six patients (23 males, 3 females; median 73.5 years) with histologically proven MPM and no curative surgery received nivolumab plus ipilimumab combination therapy. FDG-PET/CT and diagnostic CT scanning at the baseline, and after 2–4 cycles (2 in three, 3 in 17, 4 in six patients) were performed. Therapeutic response findings evaluated using imPERCIST and mRECIST were compared. PFS and OS analyses were done using log-rank and Cox methods. Results: imPERCIST indicated nine progressive metabolic disease (PMD), eight stable metabolic disease (SMD), four partial metabolic response (PMR), and five complete metabolic response (CMR) cases. mRECIST showed nine with progressive disease (PD), nine stable disease (SD), seven partial response (PR), and one complete response (CR). Although high concordance was noted (κ = 0.827), imPERCIST correctly judged a greater percentage with CMR (15.4%). Following a median 10.0 months, 15 patients showed progression and eight died from MPM. With both, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients without progression (CMR/PMR/SMD, CR/PR/SD, respectively) as compared to PMD/PD patients (imPERCIST p < 0.0001 and p = 0.015, respectively; mRECIST p < 0.0001 and p = 0.015, respectively). “For unresectable MPM patient examinations, FDG-PET and CT provide accurate findings for evaluating tumor response and also prognosis prediction following first-line nivolumab plus ipilimumab immunotherapy (approximately three cycles).” DOI - https://doi.org/10.18632/oncotarget.28594 Correspondence to - Kazuhiro Kitajima - kazu10041976@yahoo.co.jp Video short - https://www.youtube.com/watch?v=7ZRTRwig60Y About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com. MEDIA@IMPACTJOURNALS.COM

Moderator: Massimo Filippi (Milan, Italy)Guest: Federica Agosta (Milan, Italy)In this week's episode Prof. Massimo Filippi and Prof. Federica Agosta discuss frontotemporal dementia (FTD) emphasizing the role of neuroimaging (MRI and FDG PET) in early diagnosis. They highlight MRI for identifying crucial patterns and FDG PET for detecting metabolic changes. Early detection is crucial for future treatments. Connectomics, studying brain networks, aids in predicting FTD progression. Emerging PET tracers, like UCBJ, show promise for early neurodegeneration markers. The episode is a valuable resource for neurologists interested in FTD diagnostics and monitoring.

CardioNerds join Dr. Ethan Fraser and Dr. Austin Culver from the MedStar Georgetown University Hospital internal medicine and cardiology programs in our nation's capital. They discuss the following case involving an unusual case of rapidly progressive heart failure. Episode audio was edited by CardioNerds Academy Intern and student Dr. Pacey Wetstein. Expert commentary was provided by advanced heart failure cardiologist Dr. Richa Gupta. A 55-year-old male comes to the clinic (and eventually into the hospital) for what appears to be a straightforward decompensation of his underlying cardiac disease. However, things aren't as simple as they might appear. In this episode, we will discuss the outpatient workup for non-ischemic cardiomyopathy and discuss the clinical indicators that we as clinicians should be aware of in these sick patients. Furthermore, we will discuss the differential for NICM, the management of patients with this rare disease, and how this disease can mimic other cardiomyopathies. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Media - Rapidly Progressive Heart Failure Pearls - Rapidly Progressive Heart Failure The non-ischemic cardiomyopathy workup should incorporate targeted multimodal imaging, thorough history taking, broad laboratory testing, genetic testing if suspicion exists for a hereditary cause, and a deep understanding of which populations are at higher risk for certain disease states. Key Point: Always challenge and question the etiology of an unknown cardiomyopathy – do not assume an etiology based on history/patient story alone.  Unexplained conduction disease in either a young or middle-aged individual in the setting of a known cardiomyopathy should raise suspicion for an infiltrative cardiomyopathy and set off a referral to an advanced heart failure program. Key Point: Consider early/more aggressive imaging for these patients and early electrophysiology referral for primary/secondary prevention. Giant Cell Myocarditis is a rapidly progressive cardiomyopathy characterized by high mortality (70% in the first year), conduction disease, and classically presents in young/middle-aged men. Key Point: If you have a younger male with rapidly progressive cardiomyopathy (anywhere as quickly as 1-2 months, weeks in some cases) and conduction disease, consider early endomyocardial biopsy, even before other advanced imaging modalities. The Diagnosis of Giant Cell Myocarditis is time-sensitive - early identification and treatment are essential to survival. Key Point: The median timeframe from the time the disease is diagnosed to the time of death is approximately 6 months. 90% of patients are either deceased by the end of 1 year or have received a heart transplant. The treatment of Giant Cell Myocarditis is still governed largely by expert opinion, but the key components include high-dose steroids and cyclosporine, largely as a bridge to transplantation or advanced heart failure therapies. Key Point: Multi-disciplinary care is essential in delivering excellent care in the diagnostic/pre-transplant period, including involvement by cardiology, cardiac surgery, radiology, critical care, allergy/immunology, case management, advanced heart failure, and shock teams if necessary. There remains significant clinical overlap between Giant Cell Myocarditis and sarcoidosis, making managing equivocal cases challenging. Key Point: Consider early FDG-PET imaging in equivocal cases, as management during the pre-transplant period and evaluation of transplant candidacy can vary drastically between the two. Show Notes - Rapidly Progressive Heart Failure 1.

CardioNerds co-founder Dr. Dan Ambinder, series chair Dr. Teodora Donisan, and Dr. Sukriti Banthiya discuss cardiac tumors with Dr. Juan Lopez-Mattei, a nationally recognized expert in the fields of cardio-oncology and the director of cardiac imaging at the Lee Health Heart Institute. Here, we explore the topic of cardiac tumors, with a focus on distinguishing between primary and secondary tumors. We delve into the symptoms, diagnostic methods, and treatment options. Show notes were drafted by Dr. Sukriti Banthiya and episode audio was edited by CardioNerds Intern and student Dr. Diane Masket. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Cardiac Tumors Keep it simple when approaching an intracardiac mass; start with transthoracic echocardiography (TTE) and use transesophageal echocardiography (TEE) or cardiac magnetic resonance (CMR) based on the clinical context. Use TEE when suspecting valvular vegetations or thrombi & CMR for intracavitary cardiac masses. Cardiac tumors can manifest with a variety of symptoms; however, they are more commonly diagnosed as an incidental finding! When faced with the dilemma of selecting the most suitable imaging modality for evaluating a cardiac mass, consider the following hierarchy: begin with TTEas the first choice, followed by CMR. If the patient cannot undergo CMR, the next step is cardiac computed tomography (CT) or Fluorodeoxyglucose F18 positron emission tomography (FDG-PET). TEE is especially useful for the evaluation of small, highly mobile cardiac masses! Imaging cannot substitute a tissue diagnosis of cardiac masses. However, in cases of advanced malignancy, it may not always be necessary. Show notes - Cardiac Tumors Segment One: A big “picture” Approach to Cardiac Tumors Let's start with an overview of cardiac masses Neoplastic vs non-neoplasticNeoplastic lesions can be further classified into Primary Cardiac Tumors (PCT's) & Secondary Cardiac Tumor (SCT's)A majority of PCTs are benign (up to 90%!); however, rarely, they may be malignant. SCTs are more common than PCTs, and, by definition, they are malignant tumors. Now, let's look at the tools you can use to aid with the diagnosis of cardiac masses… Step 1: Investigate the cardiac mass initially with TTE. Step 2: Collect clues through history-taking & examination.If suspecting valvular vegetations (as in infective endocarditis!) or left atrial appendage thrombus, characterize the mass further with TEE.Consider the possibility of metastatic cardiac tumors in patients with a known malignancy, as they are more common than primary cardiac tumors. In cases where it is uncertain if the mass is a cardiac tumor or thrombus, use CMR to differentiate the two entities. Some findings on TTE that support the presence of a thrombus include left ventricular dysfunction with segmental wall motion abnormalities and/or apical aneurysm as these result in local pockets of stasis (think: Virchow's triad) Step 3: Put it all together! Think about whether a tissue biopsy will be needed. If yes, determine whether a negative margin or open biopsy will be required. Segment Two: Symptoms, Symptoms, Symptoms! Cardiac tumors may be symptomatic and present in the 3 key ways as outlined below (Think COD

CardioNerds meet with fellows from The Christ Hospital, Drs. Hanad Bashir, Hyunsoo Chung, and Dalia Aziz to discuss the following case that highlights angioleiomyoma: A 60-year-old woman with a past medical history significant for breast cancer (on tamoxifen) presented as a transfer to our facility for a clot-in-transit. She had initially presented to the outside hospital after progressive dyspnea on exertion and recent syncope. She was found on an echocardiogram to have a right atrial mass spanning into the right ventricle. CTA of the chest and abdomen/pelvis demonstrated extensive thrombus burden spanning from the IVC into the right ventricle. She was transferred to our facility for intervention. Endovascular attempts were unsuccessful, at which point she underwent surgical thrombectomy. Gross examination of the mass revealed a cylindrical shape, homogeneous tan color, rubbery soft tissue, measuring 25.5 cm in length and 2.3 cm in diameter. Histology confirmed the presence of angioleiomyoma. A second, smaller mass (5.2cm long and 4mm in diameter) was removed from under the tricuspid valve, with histology consistent with leiomyoma. Estrogen receptor and progesterone receptor staining were strongly positive, leading to the discontinuation of tamoxifen. Given the presence of uterine fibroids identified on the CT scan, there was concern about a uterine origin. A hysterectomy is planned for her in the near future. Expert commentary is provided by Dr. Wojciech Mazur. Episode audio was edited by student Dr. Adriana Mares. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Media - The Tall Tail Heart: Angioleiomyoma – The Christ Hospital Pearls - The Tall Tail Heart: Angioleiomyoma – The Christ Hospital Although evaluation of cardiac mass by echocardiography can provide information such as size, location, and morphology, adjunctive cross-sectional imaging may be used depending on the need for further temporal resolution (CT) or tissue characterization via cardiac MRI (CMR). If suspicious for elevated metabolic activity, there should be consideration of FDG-PET. Tamoxifen (a selective estrogen receptor modulator) is an agent used for breast cancer therapy. However, its use has been associated with endometrial hyperplasia, uterine fibroids, endometrial and uterine malignancy. Increased risk of malignancy has been seen more often in post-menopausal women and is dose and time-dependent. Clot in transient is a mobile thrombus, typically within the right heart structures. It is estimated to occur in 4-18% of patients with pulmonary embolism and is associated with elevated morbidity and mortality. Treatment includes surgical embolectomy, endovascular embolectomy, systemic thrombolysis, catheter-directed thrombolysis, or systemic anticoagulation. Angioleiomyoma is a rare benign pericystic tumor that most commonly affects the extremities. There are case reports of other affected sites, including the uterus. Invasion into the cardiac structures is exceedingly rare. The only established treatment for angioleiomyoma is surgical resection. Show Notes - The Tall Tail Heart: Angioleiomyoma – The Christ Hospital Syncope Syncope is a transient loss of consciousness secondary to reduced blood flow to the brain. Often, certain presentations are mislabeled as syncope, such as seizure disorders, posttraumatic loss of consciousness, and cataplexy. An organized diagnostic approach should be used to reduce hospital admissions and medical costs and increase diagnostic accuracy. Syncope can be divided into five general subgroups. 1) Neurally mediated reflex syncope (carotid sinus syndro...

Lobular breast cancer is cancer that starts in the lobules, the glands in the breast that produce milk. Lobular breast cancer is the second most common breast cancer, accounting for about 10% of breast cases in the United States. Lobular breast cancer doesn't always form a lump and can spread to areas of the body different from ductal breast cancer, such as the abdominal lining or the tissue around the kidneys or the eyes. Listen to the podcast to hear Dr. Jochelson explain: why lobular breast cancer is harder to see on mammograms the imaging tests used to figure out if lobular breast cancer has spread to other areas of the body the difference between a FES PET scan and a FDG PET scan

Assessing disease activity in large vessel vasculitis can be a challenge. And as imaging techniques evolve, clinicians must evaluate how to harness new imaging modalities in clinical care. In an attempt to predict the progression of large vessel vasculitis (LVV), our next guest, Dr. Kaitlin Quinn, used the vascular activity seen on a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan to determine if there is an observable association with angiographic change. Dr. Quinn, author of the study Association of 18F-Fluorodeoxyglucose–Positron Emission Tomography Activity With Angiographic Progression of Disease in Large Vessel Vasculitis, breaks down her study and its methods along with her observations and findings for us. 

Go online to PeerView.com/NEF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Alzheimer's disease (AD) is a devastating and highly prevalent condition, affecting 10% of people over 65 years of age, and increasing in prevalence as the population ages. Given the heavy economic and social burdens of AD, major emphasis has been placed on finding disease-modifying therapies (DMTs) that can address the underlying pathophysiology and prevent, delay, slow, or halt the inexorable decline of AD. Now, after almost two decades without a new AD treatment, recent advances in DMTs, including the accelerated approval from the FDA of two amyloid-targeting therapies (ATTs) and a third in late-stage development, have opened the door to the possibility of reductions in disease progression and improved patient outcomes. In order for these treatments to be successful, initiation in the prodromal or early symptomatic stages of AD is critical. Fortunately, significant advances have been made in the development and validation of molecular imaging techniques that may aid in an early diagnosis. It is therefore imperative that clinicians remain aware of the evolving role of molecular imaging tools (eg, amyloid PET, FDG PET, tau PET) and PET quantification techniques in the early diagnosis of AD, and are prepared to integrate these diagnostic tools into clinical practice. At a recent PeerView educational event, a panel of AD experts illustrated how to integrate validated and emerging neuroimaging biomarkers and quantitative measures into clinical practice to facilitate AD diagnosis. Through a case-based discussion, the faculty offered learners an in-depth look at the complex diagnostic challenges associated with early AD and mild cognitive impairment, and provided practical guidance on effectively and appropriately incorporating these strategies into patient care. You can now watch this on-demand version of the event! Upon completion of this activity, participants should be better able to: Employ molecular imaging tools to optimize the timely and accurate neuropathological diagnosis of AD; and Apply quantitative analysis to augment the visual interpretation of PET imaging in AD

Go online to PeerView.com/NEF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Alzheimer's disease (AD) is a devastating and highly prevalent condition, affecting 10% of people over 65 years of age, and increasing in prevalence as the population ages. Given the heavy economic and social burdens of AD, major emphasis has been placed on finding disease-modifying therapies (DMTs) that can address the underlying pathophysiology and prevent, delay, slow, or halt the inexorable decline of AD. Now, after almost two decades without a new AD treatment, recent advances in DMTs, including the accelerated approval from the FDA of two amyloid-targeting therapies (ATTs) and a third in late-stage development, have opened the door to the possibility of reductions in disease progression and improved patient outcomes. In order for these treatments to be successful, initiation in the prodromal or early symptomatic stages of AD is critical. Fortunately, significant advances have been made in the development and validation of molecular imaging techniques that may aid in an early diagnosis. It is therefore imperative that clinicians remain aware of the evolving role of molecular imaging tools (eg, amyloid PET, FDG PET, tau PET) and PET quantification techniques in the early diagnosis of AD, and are prepared to integrate these diagnostic tools into clinical practice. At a recent PeerView educational event, a panel of AD experts illustrated how to integrate validated and emerging neuroimaging biomarkers and quantitative measures into clinical practice to facilitate AD diagnosis. Through a case-based discussion, the faculty offered learners an in-depth look at the complex diagnostic challenges associated with early AD and mild cognitive impairment, and provided practical guidance on effectively and appropriately incorporating these strategies into patient care. You can now watch this on-demand version of the event! Upon completion of this activity, participants should be better able to: Employ molecular imaging tools to optimize the timely and accurate neuropathological diagnosis of AD; and Apply quantitative analysis to augment the visual interpretation of PET imaging in AD

Go online to PeerView.com/NEF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Alzheimer's disease (AD) is a devastating and highly prevalent condition, affecting 10% of people over 65 years of age, and increasing in prevalence as the population ages. Given the heavy economic and social burdens of AD, major emphasis has been placed on finding disease-modifying therapies (DMTs) that can address the underlying pathophysiology and prevent, delay, slow, or halt the inexorable decline of AD. Now, after almost two decades without a new AD treatment, recent advances in DMTs, including the accelerated approval from the FDA of two amyloid-targeting therapies (ATTs) and a third in late-stage development, have opened the door to the possibility of reductions in disease progression and improved patient outcomes. In order for these treatments to be successful, initiation in the prodromal or early symptomatic stages of AD is critical. Fortunately, significant advances have been made in the development and validation of molecular imaging techniques that may aid in an early diagnosis. It is therefore imperative that clinicians remain aware of the evolving role of molecular imaging tools (eg, amyloid PET, FDG PET, tau PET) and PET quantification techniques in the early diagnosis of AD, and are prepared to integrate these diagnostic tools into clinical practice. At a recent PeerView educational event, a panel of AD experts illustrated how to integrate validated and emerging neuroimaging biomarkers and quantitative measures into clinical practice to facilitate AD diagnosis. Through a case-based discussion, the faculty offered learners an in-depth look at the complex diagnostic challenges associated with early AD and mild cognitive impairment, and provided practical guidance on effectively and appropriately incorporating these strategies into patient care. You can now watch this on-demand version of the event! Upon completion of this activity, participants should be better able to: Employ molecular imaging tools to optimize the timely and accurate neuropathological diagnosis of AD; and Apply quantitative analysis to augment the visual interpretation of PET imaging in AD

Go online to PeerView.com/NEF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Alzheimer's disease (AD) is a devastating and highly prevalent condition, affecting 10% of people over 65 years of age, and increasing in prevalence as the population ages. Given the heavy economic and social burdens of AD, major emphasis has been placed on finding disease-modifying therapies (DMTs) that can address the underlying pathophysiology and prevent, delay, slow, or halt the inexorable decline of AD. Now, after almost two decades without a new AD treatment, recent advances in DMTs, including the accelerated approval from the FDA of two amyloid-targeting therapies (ATTs) and a third in late-stage development, have opened the door to the possibility of reductions in disease progression and improved patient outcomes. In order for these treatments to be successful, initiation in the prodromal or early symptomatic stages of AD is critical. Fortunately, significant advances have been made in the development and validation of molecular imaging techniques that may aid in an early diagnosis. It is therefore imperative that clinicians remain aware of the evolving role of molecular imaging tools (eg, amyloid PET, FDG PET, tau PET) and PET quantification techniques in the early diagnosis of AD, and are prepared to integrate these diagnostic tools into clinical practice. At a recent PeerView educational event, a panel of AD experts illustrated how to integrate validated and emerging neuroimaging biomarkers and quantitative measures into clinical practice to facilitate AD diagnosis. Through a case-based discussion, the faculty offered learners an in-depth look at the complex diagnostic challenges associated with early AD and mild cognitive impairment, and provided practical guidance on effectively and appropriately incorporating these strategies into patient care. You can now watch this on-demand version of the event! Upon completion of this activity, participants should be better able to: Employ molecular imaging tools to optimize the timely and accurate neuropathological diagnosis of AD; and Apply quantitative analysis to augment the visual interpretation of PET imaging in AD

I am thrilled to announce our latest podcast episode featuring Dr. Heather Jacene and Dr. Jennifer Specht.  In this episode, we dive into the topic of nuclear medicine and its role in breast cancer treatment.Dr. Jacene, Assistant Chief of Nuclear Medicine at Brigham and Women's Hospital and Clinical Director of Nuclear Medicine at Dana-Farber Cancer Institute shares her expertise on the latest advancements in nuclear medicine and how it can be used to detect and treat breast cancer. Dr. Specht, a medical oncologist who specializes in caring for patients with all stages of breast cancer., also joins us to provide insights on the patient experience and how nuclear medicine plays a critical role in monitoring treatment. Topics in this Episode:[00:02:31] Radio tracers for cancer therapy. [00:03:23] Nuclear medicine imaging. [00:09:17] FDG PET scan for cancer. [00:10:57] Nuclear medicine for breast cancer. [00:14:42] FDG PET scan for breast cancer. [00:18:12] Breast cancer and bone attraction. [00:21:33] FDG PET scan for bone metastases. [00:25:21] Clinical trials for breast cancer. [00:30:07] Imaging for Early Stage Disease. [00:32:51] Cancer treatment and response rates. [00:35:58] Therapeutic nuclear medicine. [00:40:27] Nuclear medicine misconceptions. [00:43:06] Getting involved with Surviving Breast Cancer.As always, our podcasts are made possible thanks to donations from listeners like you. If you would like to support our nonprofit organization, please consider making a contribution through survivingbreastcancer.org/donate.Don't forget to also check out all of our free programming and services available to anyone who has been diagnosed with breast cancer. Visit survivingbreastcancer.org/events for more information.Thank you for being a part of our community and for supporting our mission to empower those diagnosed with breast cancer and their caregivers.Support the show

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.24.521746v1?rss=1 Authors: Meneghetti, M., Gudmundsen, F., Jessen, N. S., Sui, K., Baun, C., Palner, M., Markos, C. Abstract: The combination of neuroimaging and targeted neuromodulation is a crucial tool to gain a deeper understanding of neural networks at a circuit level. Infrared neurostimulation (INS) is a promising optical modality that allows to evoke neuronal activity with high spatial resolution without need for the introduction of exogenous substances in the brain. Here, we report the use of whole-brain functional [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging during INS in the dorsal striatum, performed using a multifunctional soft neural probe. We demonstrate the possibility to identify multi-circuit connection patterns in both cortical and subcortical brain regions within a single scan. By using a bolus plus infusion FDG-PET scanning protocol, we were able to observe the metabolic rate evolution in these regions during the experiments and correlate its variation with the onset of the INS stimulus. Due to the focality of INS and the large amount of viable molecular targets for PET, this novel approach to simultaneous imaging and stimulation is highly versatile. This pilot study can pave the way to further understand the brain connectivity on a global scale. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This month on Episode 41 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the September 30 and October 14 issues of Circulation Research. This episode also features an interview with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, to discuss their study, Transcriptional and Immune Landscape of Cardiac Sarcoidosis.   Article highlights:   Tian, et al. EV-Mediated Heart Brain Communication in CHF   Wleklinski, et al.  Impaired Dynamic SR Ca Buffering Causes AD-CPVT2   Masson, et al. Orai1 Inhibition as a Treatment for PAH   Li, et al. F. Prausnitzii Ameliorates Chronic Kidney Disease   Cindy St. Hilaire:        Hi, and welcome to Discover Circ Res, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to highlight articles from our September 30th and October 14th issues of Circulation Research.                                           I'm also going to have a chat with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to discuss their study Transcriptional and Immune Landscape of Cardiac Sarcoidosis. But before I get to the interview, I'm going to highlight a few articles.   Cindy St. Hilaire: The first article I'm going to share is Extracellular Vesicles Regulate Sympathoexcitation by Nrf2 in Heart Failure. The first author of this study is Changhai Tian, and the corresponding author is Irving Zucker, and they are at University of Nebraska. After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling, and ultimately, heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI, likely due to upregulation of Nrf2-targeting microRNAs. These microRNAs can also be packaged into vesicles and released from stressed heart cells.   Now, this group has shown that rats and humans with chronic heart failure have an abundance of these microRNA-containing EVs in their blood. In the rats with chronic heart failure, these extracellular vesicles were found to be taken up by neurons of the rostral ventrolateral medulla, RVLM, wherein the microRNA suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system, and in the presence of EVs, it is ramped up by sympathetic excitation. Because such elevated sympathetic activity can induce the fight or flight response, including increased heart rate and blood pressure, this would likely worsen heart failure progression. The team, however, found that inhibiting microRNAs in the extracellular vesicles prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically.   Cindy St. Hilaire:        The next article I want to highlight is titled, Impaired Dynamic Sarcoplasmic Reticulum Calcium Buffering in Autosomal Dominant CPVT2. The first author of this study is Matthew Wleklinski, and the corresponding author is Bjӧrn Knollmann, and they are at Vanderbilt University.   Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure, and other features of the fight or flight response. For people with catecholaminergic polymorphic ventricular tachycardia, or CPVT, physical activity or stress can cause potentially lethal arrhythmias. Mutations of calsequestrin-2, or CASQ2, which is a sarcoplasmic reticulum calcium-binding protein, is a major cause of CPVT, and can be recessive or dominant in nature.   For many recessive mutations, disease occurs due to loss of CASQ2 protein. This group investigated a dominant lysine to arginine mutation in this protein, and found by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so, too, was the protein's subcellular localization. The mutation instead interfered with CASQ2's calcium binding or buffering capability within the sarcoplasmic reticulum. The result was that upon catecholamine injection or exercise, the unbound calcium released prematurely from the sarcoplasmic reticulum, triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations.   Cindy St. Hilaire:        The next article I want to highlight is from our October 14th issue of Circulation Research, and the title of the article is ORAI1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. The first author is Bastien Masson, and the corresponding author is Fabrice Antigny, and they're from Inserm in France. In pulmonary arterial hypertension, the arteries of the lungs become progressively obstructed, making it harder for the heart to pump blood through them, ultimately leading to right ventricular hypertrophy and heart failure. A contributing factor in the molecular pathology of pulmonary arterial hypertension is abnormal calcium handling within the pulmonary artery smooth muscle cells. Indeed, excess calcium signaling causes these cells to proliferate, migrate, and become resistant to apoptotic death, thus leading to narrowing of the vessel.   This group now identified the calcium channel ORAI1 as a major culprit behind this excess signaling. Samples of lung tissue from pulmonary arterial hypertension patients and a pulmonary arterial hypertension rat model had significantly upregulated expression of this channel compared with controls. And in patient pulmonary arterial smooth muscle cells, the high ORAI1 levels resulted in heightened calcium influx, heightened proliferation, heightened migration and reduced apoptosis. Inhibition of ORAI1 reversed these effects. Furthermore, in pulmonary hypertension model rats, ORAI1 inhibition reduced right ventricle systolic pressure and attenuated right ventricle hypertrophy when compared with untreated controls. This study indicates that ORAI1 inhibitors could be a new potential target for treating this incurable condition.   Cindy St. Hilaire:        The last article I want to share is titled Faecalibacterium Prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis. The first author of this study is Hong-Bao Li, and the corresponding author is Tao Yang, and they are from the University of Toledo.   Progressive renal inflammation and fibrosis accompanied by hypertension are hallmarks of chronic kidney disease, which is an incurable condition affecting a significant chunk of the world's population. Studies indicate that chronic kidney disease is linked to gut dysbiosis. Specifically, depletion of lactobacillus bifidobacterium and faecalibacterium, prompting investigations into the use of probiotics. While supplements including lactobacillus and bifidobacterium have shown little effectiveness in chronic kidney disease, supplementations with F. prausnitzii have not been investigated.   Now, this group has shown in a mouse model of chronic kidney disease that oral administration of F. prausnitzii has beneficial effects on renal function, reducing renal fibrosis and inflammation. This bacterial supplementation also produced the short chain fatty acid butyrate, which was found to be at unusually low levels in the blood samples from the CKD model mice and from chronic kidney disease patients. Oral supplementation with this bacterium boosted butyrate levels in the mice, and in fact, oral administration of butyrate itself mimicked the effects of the bacteria. These findings suggest that supplementation with F. prausnitzii or, indeed, butyrate could be worth investigating as a treatment for chronic kidney disease.   Cindy St. Hilaire:        Today I have with me Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to talk about their paper, Transcriptional and Immune Landscape of Cardiac Sarcoidosis. This is in our September 30th issue of Circulation Research. Welcome, and thank you for taking the time to speak with me today.   Chieh-Yu Lin:             Thank you for inviting us. It's a great honor to be here today.   Kory Lavine:               Thank you.   Cindy St. Hilaire:        Really great paper, ton of data, and hopefully, we can pick some of it apart. But before we get into it, I actually want to just talk about sarcoidosis generally. I know it's a systemic inflammatory disease that has this kind of aggregation of immune cells as its culprit, and it can happen in a bunch of different organs. It's mostly in the lung, but it's also, like you're studying, in the heart. Can you just give us a little bit of background? What is sarcoidosis, and how common is cardiac sarcoidosis?   Chieh-Yu Lin:             Well, this is actually a great question, and I'll try to answer it. You actually capture one of the most important kind of features for sarcoidosis. It happens in all kind of organ system, mostly commonly in lung, in lymph nodes, but also in heart, spleen, even in brain, or even orbit, like eyes. It's really a truly multisystemic disease that has been characterized by this aggregate of macrophages, or myeloid cells, with scattered multinucleated giant cells, as the name implies, have multiple nuclear big, chunky, cells that form an aggregate. That's kind of like a pathognomonic feature for sarcoidosis, whether it's happening in lung, in the heart. When any organ system, a lot of studies has been done, but as of now, a very clear pathogenesis or mechanism has been, I would say, still pretty elusive, or still remain quite unclear, despite all the great effort has been made in this field. The other thing is that a lot of the studies actually focusing on pulmonary sarcoidosis for good reasons. Actually, that's one of the most common manifestations. For cardiac sarcoidosis, although it's only effect in probably, I would say depends on the data, 20% to 30% of the outpatient that with sarcoidosis, with or without lung involvement. It's actually carry a very significant clinical implications as of matter that the presentation of cardiac sarcoidosis can be devastating and sometimes actually fatal. Some of the study actually show that cardiac sarcoidosis actually higher, up to 80%, just because the first presentation's actually, unfortunately, sudden cardiac death. That's why Kory and I, we teamed up. I'm a cardiothoracic pathologist, so in my clinical practice I see specimens and samples from human body, from patient suffer from sarcoidosis, both in lung, lymph node, and heart. Kory is an outstanding heart failure, heart transplant cardiologist, see the other end, which is the patient care. This disease, specifically in heart, its presentation and its pathogens in heart, really attracts our attention.   Cindy St. Hilaire:        Do we know any or some of the potential causes? Why it would start, maybe in a different patient population, but also in the heart versus the lung? Do we know anything about that process?   Kory Lavine:              We know nothing about it. Sarcoid has no known etiology. There's been thoughts in the past that it may be driven by infection, the typical pathogens or autoimmune ideologies, but really, there's little data out there to support those possibilities. Right now, the field's wide open. The other challenge is we don't really have a good way to treat this disease, so a lot of the therapies available are things like steroids, which can have some effect on the disease but carry a lot of risk of complications. The other agents that we sometimes use to lower the doses of steroids, things like methotrexate and azathioprine, are only modestly effective.   These are really the motivation for Chieh-Yu and myself to pursue this. We don't really know what causes the disease, and we don't really have very good treatments. We really wanted to take the first step, that's to study the real disease, and understand what are the pathologic cell types that are present within the granuloma, which is these aggregation of immune cells that Chieh-Yu was speaking about.   Cindy St. Hilaire:        What is actually happening at the beginning of this disease? These granulomas form, and then what is the pathological progression in the heart? What goes on there?   Chieh-Yu Lin:             This is actually another great question that I will say there's not much that has been discovered because, especially in human tissue, every time we have a sample, it's actually a kind of time point. We cannot do a longitudinal study. But in general speaking, very little is known about how it's initiated because it will need to accumulate to a certain disease burden for this to have a clinical symptom sign and be manifested, and then being clinically studied. We do know that in both heart and lung after treatment of progressions, it's usually in, a general speaking, going through a phase from a more proliferative means that it's creating more granulomas, more  inflammatory cell aggregate, to a more fibrotic phase. Means that sometimes you actually see the granuloma start to disappear or dissipate, and then showing this kind of dense collagen and fibrosis. That has been commonly documented in both lung and heart sarcoidosis. The other things is that very difficult to study this disease that we do not have a great animal model, so we cannot use animal model to try to approximate or really study the disease pathogenesis. There are several animal models they try to use microbacteria or infectious agents, and these infectious agents can create morphologically similar granuloma, per se, but just like in human body. For instance, patients suffer from TB in their lung, biopsy will show this. But clinically, these are two very distinct disease entities, even though they look alike. Even in the heart, one of the conditions that we study in our paper is giant cell myocarditis, as the name implying having multinucleated giant cells granuloma. It looks really alike under microscopy for pathologists like me, but their clinical course in response to treatment is drastically different. This type of barriers and in the current limitations of our study tool makes, as Kory just said, this is really a wide open. We just know so little despite all the effort.   Cindy St. Hilaire:        Yeah. I'm guessing based on this granuloma information, to start with, the obvious question you went after is going after the immune cell populations that possibly contribute to sarcoidosis. To do this, because you have the human tissue, you went for single cell transcriptional profiling, which is a great use of the technology. But what biological sources did you use, and how did you go about choosing patient? Because the great thing about single cell is you can do just that, you can look at however many thousands of cells in one patient. But how do you make sure or check that that is broadly seen versus just a co-founding observation in that patient?   Kory Lavine:               We use explanted hearts and heart tissue from patients that underwent either heart transplantation or implementation of LVADs. It's a pretty big hunk of myocardium, and we're lucky to work with outstanding pathologists both at WashU, JU, as well as our collaborators at Duke. Between the two institutions, we're able to pull together a collection of tissues where we knew there were granulomas within that piece of tissue we analyzed. You bring up an important challenge. You need to make sure the disease and cause of the disease is present in the tissue that you're analyzing, otherwise you'll not come up with the data that really is informative.   Chieh-Yu Lin:             Kory beautifully answered the question, but I just wanted to add one little thing, and that's also why we use various different modalities. Some of them is more inside you, like the NanoString Technologies' spatial transcriptomic. You can visualize and confirm that we are studying the phenomenon that has been described for sarcoidosis, and then using multichannel immunofluorescence to validate our sequencing data, to complement such limitations of certain technology.   Cindy St. Hilaire:        Especially, I feel like with this diseased tissue that it's such a large tissue, there's so much information, it's really hard to dig in and figure out where the signal is. This was a wonderful paper for kind of highlighting, integrating all these new technologies with also just classical staining. Makes for great pictures as well. How does this cellular landscape of cardiac sarcoidosis compare to a normal heart? What'd you find?   Chieh-Yu Lin:             This is a great question. Compared to normal heart, we have been talking about this accumulation of macrophages with scattered multinucleated giant cells. For the similar landscape, first and foremost, you do not see those type of accumulations in brain microscopy or by myeloid markers in the heart. Although, indeed, in even normal heart tissue we have rest and macrophages. It just doesn't form such morphological alterations. But then we dive deep into it, and then we found that from a different cell type perspective, we realized that the granuloma is composed by several different type of inflammatory cells, with most of the T cells and NKT cells kind of adding periphery. The myeloid cells, including the multinucleated giant cells also, are kind of in the center of the granuloma of the sarcoidosis. Then, we further dive in and realize that there are at least six different subtype of myeloid cells that is contributing to the formation of this very eye-catching distinctive granular malformations, and to just never feel first off and foremost, of course, is those multinucleated giant cells that is really distinct, even on the line microscopy] routine change stand.   And then we have a typical monocyte that's more like a precursor being recently recruited to the heart, and we finally sent the other four different type of myeloid cell that carry different markers, and then improving the resident macrophages. Especially for me as a pathologist, I'm using my eye and looking at stand every day, is actually these six type of cells, myeloid cells, actually form a very beautiful special kind of distribution with the connections or special arrangement with all different type, kind of like multinucleated giant cell in the middle, flanked by HLA-DR positive epithelioid macrophages, kind of scatter, and then with dendritic cells and a typical monocyte at the peripheral, and then resident macrophage kind of like in the mix of the seas of granuloma information. All these are distinct from normal heart tissues that does carry a certain amount of macrophages, but just don't form this orchestrated architectural distinct structure that's composed of this very complicated landscape.   Cindy St. Hilaire:        Those images, I think it was figure six, it's just gorgeous to look at, the model you made. One of the questions I was thinking is there must be a significance between these cells that are on the periphery and those that are in the center of this granuloma. Do you have an idea or can we speculate as to are some more cause and some more consequence of the granuloma? Were you able to capture any more information about maybe the initiating steps of these from your study?   Kory Lavine:              That's a great question, and a question the field has had for a long time. Now, we know there's different populations of cells. The single cell data allows us to understand what are the transcriptional differences and distinctions between them to gain some insights. One thing that we do know from the field is that disease activity correlates with mTOR activity within these granulomas. We took advantage of phospho-S6 kinase staining as a downstream marker of mTOR activity, and Ki-67 is a marker of self proliferation.   Which of these populations within the granuloma might be most active with respect to mTOR and respect to proliferation? If you ask most people in the field, they would jump up and say, "It's the giant cell in the middle." We found that that's not actually the case at all. It's the macrophages that surround the giant cell, the ones that are HLA-DR positive, the epithelioid macrophages, and the ones that are SYLT-3 positive that are scattered around them. That's really interesting and could make a lot of sense, and leads to hypothesis that perhaps activation mTOR signaling within certain parts of the granuloma might be sufficient to set up the rest of the architecture. That's something that we can explore in animal models, and are doing so to try to create a cause and effect relationship. Cindy St. Hilaire:        Yeah, and I was actually thinking about this, too, in relation to kind of the resident macrophages versus infiltrating macrophages or even just infiltrating immune cells. Do you know the original source of the cells that make up the granuloma? Is it mostly resident immune, or are they recruited in?   Kory Lavine:               We can make predictions from the single cell data where you can use trajectory analysis to make strong predictions about what the origin of different populations might be. What those analyses predicted is that the giant cells and the cells that surround the giant cells, the HLA-DR positive and SYLT-3 positive macrophages, come from monocytes. That's the prediction, and, of course, resident macrophages do not. However, that prediction has to be tested, and that's the beauty and importance of developing animal models. The wonderful thing today is we now have genetic tools to do that. We can ask that question.   Cindy St. Hilaire:        I don't know. Maybe you don't want to spoil the lead of the next paper, but what kind of mouse model are you thinking about trying?   Kory Lavine:               Yeah. First of all, let me talk about the tools that are available, because they're published in Circulation Research, of course. We have a nice tool to specifically mark, track and delete in tissue resident macrophages using a CX3CR1 ERT pre-mouse, and taking advantage of the concept that tissue macrophages don't turn over from monocytes and turn over from themselves. We can give tamoxifen to label all monocytes macrophages in Dcs with that CRE, and then wait a period of time where only the resident macrophages remain labeled. We can use that trick to modulate mTOR signaling as a first step, and ask whether mTOR signaling is required in that population. We've now developed a new genetic tool to do the same thing in just recruited macrophages.   Cindy St. Hilaire:        What was the most challenging aspect of this study? There's a lot of moving parts. I'm sure probably the data analysis alone is challenging, but what would you say is the most challenging?   Kory Lavine:               I think you alluded to this early on, but the most challenging thing is collecting the right tissues to analyze, and that's not a small feat or a small effort here. All the technologies are a lot of fun, and everything works so well today compared to many years ago when we trained, so it's an exciting time to do science. The most challenging and time-consuming component was assembling a group of tissues that we could do single-cell sequencing on between our group and our colleagues at Duke, and then creating validation cohorts that we did across several different institutions, including our own as well as Stanford. That team effort in building that team is the most important, challenging, and honestly, enjoyable part of this.   Chieh-Yu Lin:             I cannot agree more what Kory just said. I think that that's the challenging and the fun part, and that we're very fortunate to really have a great team to tackle this questions in multiple from multiple institute. I just want to add one more thing that, particularly for me as a cardiopathologist, one of the hardest things is I've known how to look or diagnose sarcoidosis for years, but seeing the data emerging that is so complicated and then beyond my reliable eyes in understanding, it's kind of mentally very challenging but very fun to really open and broaden the vision. It's not just how it looks like just giant cells in macrophages.   Cindy St. Hilaire:        What do you think about in terms of diagnostics or even potential therapies? How do you think this data that you have now can be leveraged towards those objectives, whether it's screening for new cell types that are really key to this granuloma formation versus therapeutically targeting them?   Kory Lavine:              This study opens new doors, and right now, diagnosis of sarcoids islimited by trying to biopsy, which, in the heart, is limited by sample bias. You certainly can biopsy the wrong area because you don't know whether a granuloma is in the area or not. We do do some cardiac and other imaging studies like FDG-PET scans, which are helpful but are not perfect, and each of them has their individual limitations. One of the beauties of our study is it identifies new markers of macrophage populations that live within the granuloma, many of which are unique to this disease.   That suggests that there's maybe an opportunity to develop imaging tracers that can identify those populations more specifically than our current PET imaging studies do, which rely simply on glucose uptake. It also opens up the possibility that we may able to take blood samples and identify some of these cell types within the blood, and have more simple testing for our patients. I think in terms of therapy, you alluded to it earlier, these concepts about mTOR signaling, that could be a new therapeutic avenue that needs to be rigorously explored in preclinical models. We're lucky already to have very good mTOR inhibitors available in clinical practice today.   Cindy St. Hilaire:        Obviously, opening new doors is amazing because it's more information, but often a good study leads to even more questions to be asked. What question, or maybe what questions, are you guys going to go after next?   Chieh-Yu Lin:             Well, that list is very long, and then that's actually the exciting thing about doing this research. There's no bad questions, in some sense. All the way from diagnosis, management, monitoring, therapeutic, how we predict where the patient can respond, that's the whole clinical side. Even the basic science side, we still haven't really answered the question, although our data suggests where that multinucleated giant cells coming from. It's very eye catching. How do they form, even though our data suggests it's from the recruited macrophages. But that's still a long way from the recruited macrophage,  monocyte to that gigantic bag of nuclei in the very fluffy cytoplasm.   And then, how the granuloma, as we discussed earlier in this discussion, really initially from a relatively normal background myocardium to form this disease process. There are just so many questions that we can ask. There are, of course, several fronts that we would like to focus on. Kory already nicely listed some of them. First and foremost is actually to establish animal model to enable us to do more details in mechanistic studies, because human tissue, as good as it is, it's kind of like a snapshot, just one time point, and it really limits our ability to test our hypothesis. Animal model, certainly, is one of the major directions that we are going forward, but also the other side, like more clinical science also to develop novel noninvasive methodologies to diagnose and to hopefully monitor this patient population in a better way.       Cindy St. Hilaire:        Well, it's beautiful work. I was actually reading this paper this weekend at a brunch place just next door to my house, and the guy sitting next to me happened to see over my shoulder the title and said that his father had passed away from it. This is hopefully going to help lots of people in the future, and really help to make the models that we need to ask, "What's happening in this disease?" Thank you so much for taking the time to speak with me, and congratulations on what seems to be a landmark study in understanding what's going on in this disease.   Chieh-Yu Lin:             Thank you so much. It's a pleasure.   Cindy St. Hilaire:        That's it for our highlights from the September 30th and October 14th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page, and follow us on Twitter and Instagram with the handle @CircRes, and hashtag Discover Circ Res. Thank you so much to our guests, Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover Circ Res, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors of the American Heart Association. For more information, please visit ahajournals.org.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.15.508088v1?rss=1 Authors: Pak, K., Malen, T., Santavirta, S., Shin, S., Nam, H. Y., De Maeyer, S., Nummenmaa, L. Abstract: Background: Ageing and clinical factors impact brain glucose metabolism. However, there is a substantial variation of the reported effects on brain glucose metabolism across studies due to the limited statistical power and cross-sectional study designs. Methods: We retrospectively analyzed data from 441 healthy males (mean 42.8, range 38-50 years) who underwent health check-up program twice at baseline and 5-year follow-up. Health check-up program included 1) brain 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET), 2) anthropometric and body composition measurements, 3) blood samples, and 4) questionnaires for stress and depression. After spatial normalization of brain FDG PET scans, standardized uptake value ratio (SUVR) was measured from 12 region-of-interests. We used hierarchical clustering analysis to reduce their dimensionality before the Bayesian hierarchical modelling. Five clusters were established for predicting regional SUVR; 1) metabolic cluster (body mass index, waist-to-hip ratio, fat percentage, muscle percentage, homeostatic model assessment index-insulin resistance), 2) blood pressure (systolic, diastolic), 3) glucose (fasting plasma glucose level, HbA1c), 4): psychological cluster (stress, depression), and 5) heart rate. The effects of clinical variable clusters on regional SUVR were investigated using Bayesian hierarchical modelling with brms that applies the Markov-Chain Monte Carlo sampling tools. Results: All the clinical variables except depression changed during the 5-year follow-up. SUVR decreased in caudate, cingulate, frontal lobe and parietal lobe and increased in cerebellum, hippocampus, occipital lobe, pallidum, putamen, temporal lobe and thalamus. SUVRs of thalamus, pallidum, hippocampus, putamen and parietal lobe were negatively associated with metabolic cluster and the effects of glucose on SUVRs varied across regions. SUVRs of thalamus, hippocampus, cingulate, cerebellum increased and those with occipital lobe decreased with heart rate. The effects of blood pressure and psychological cluster markedly overlapped with zero across regions. Conclusion: Regionally selective decline in brain glucose utilization begins already in the middle age, while individual differences in brain glucose metabolism remain stable. In addition to ageing, brain glucose utilization is also associated with metabolic cluster, blood glucose levels and heart rate. These effects are also consistent over the studied period of 5 years in the middle adulthood. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

A study looking at people with genetic variants that mimic the effect of statins and PCSK9 inhibitors showed significantly worse cognition and brain area among those with the statin variants. This suggests that statins may negatively impact the brain (PMID 35953131).This suggests that important benefits to cerebrovascular disease may be counterbalanced by other negative effects on the brain by statins through other mechanisms.An important caveat to the study is that while these statin-mimicking variants are expressed everywhere in the body in people who have inherited them, different statins have a different degree of selectivity for the liver versus other tissues (such as the brain).Statins that are selective for the liver are called hydrophilic, while those that are nonspecific and inhibit HMGCR in all tissues (including the brain) are called lipophilic.This is because lipophilic statins freely travel across cell membranes, while hydrophilic statins need to be transported into liver cells using transporters (OATP1B1, OATP1B3, OATP2B1, BCRP, and MRP2) expressed only in the liver (PMID: 29051147).Interestingly, another recent study found that statin users with mild cognitive impairment using lipophilic statins had an increased risk of converting to dementia compared to non-users and users of hydrophilic statins (https://jnm.snmjournals.org/content/62/supplement_1/102).This same study found using FDG PET a decline in metabolism in several regions of the brain important for cognition in those using lipophilic statins but not non-users or users of hydrophilic statins.While no strong, gold standard evidence implicates lipophilic statins as harmful for brain health, given the wide availability of similarly priced alternatives, these findings might suggest that hydrophilic statins should be preferred to lipophilic ones whenever possible. The hydrophilic statins are pravastatin (Pravachol) and rosuvastatin (Crestor), while the lipophilic statins are fluvastatin (Lescol), lovastatin (Mevacor, Altoprev), simvastatin (Zocor), atorvastatin (Lipitor), and pitavastatin (Livalo).===Like, comment, subscribe.For more, find me at:PODCAST The Kevin Bass ShowYOUTUBE https://www.youtube.com/user/kbassphiladelphiaSUBREDDIT www.reddit.com/r/kevinbassWEBSITE http://thedietwars.comTWITTER https://twitter.com/kevinnbass/https://twitter.com/healthmisinfo/INSTAGRAM https://instagram.com/kevinnbass/TIKTOK https://tiktok.com/@kevinnbassAnd above all, please donate to support what I do:PATREON https://patreon.com/kevinnbass/DONATE https://thedietwars.com/support-me/

Dr. Hilmar Sigurdsson shares the results of an FDG PET study that found 2 distinct patterns of brain metabolism related to gait disfunction in PD, suggesting that this objective measure could help better understand the neural basis of gait disorders and could also be used to predict gait involvement in clinical practice and as outcome measure in clinical trials. Read the article.

Not to be confused with “carcinoma of unknown primary,” in this episode of metastatic disease of “origin TBD”, we discuss the workup of a mass noted incidentally on imaging. This is a very high yield topic often faced on solid oncology consults! Major Points Covered:Mass found incidentally on imaging → we need to stage alwaysInitial Workup:Reasonable to get CBC, CMP, UA, PSA (if male)Low blood counts, maybe marrow involvementCr elevated concern for obstruction possiblyLFTs elevated concern for mass in the biliary/pancreas regionUA w/ hematuria → maybe bladderBut bottom line you're gonna get a scan, which scan to get though?Recommend referencing NCCN guidelines to determine additional staging scansCreate an account on nccn.org and look at guidelines by tumor typeNot all cancers require a PET/CT scanThere are newer modalities for imaging other than FDG PET including PSMA PET (prostate), Auxumin PET (prostate), and DOTATE PET (neuroendocrine)Certain cancers can be diagnosed on imaging alone (RCC and HCC)Some cancers require Brain MRI for stagingWhat to biopsy?FNA often adequate for solid tumors but may need core if non diagnostic Need core or ideally excisional if highly concerned for lymphomaAlways try to biopsy the site that will upstageDistant lymph nodes or other metastatic sitesWhat about tumor markers?We use this for treatment monitoring, not for diagnostic purposesImportant to establish a baseline to follow, special circumstances for diagnostic purposes to consider below:PSA in male if concerned about prostate cancerAFP helpful if concerned for HCC → liver masses in a cirrhoticAFP and b-HCG if concerned for testicular → young or middle aged male with mediastinal massMolecular testing not necessarily needed at the time of biopsy Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

Confused about scans? NET expert Dr Gary Ulaner answers the top 10 questions about imaging for NETs. Dual board-certified in radiology and nuclear medicine, Dr. Ulaner explains different scans used in NET imaging including functional imaging scans such as Gallium-68 DOTATATE, Copper-64 DOTATATE, and FDG PET scans and anatomical scans such as MRI and CT scans. He addresses common questions about radiation safety, contrasts, and SUV. Listen now!For more information, visit LACNETS.org.

Guest host, Dr. Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, and Dr. Jason Efstathiou, chair of the 2022 ASCO Genitourinary Cancers Symposium, discuss key abstracts and innovations in GU oncology featured at #GU22. Dr. Efstathiou is professor at Harvard Medical School and director of the Genitourinary Division in Radiation Oncology at Massachusetts General Hospital.   Transcript Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Program and professor of medicine at the University of Utah Huntsman Cancer Institute and editor in chief of the ASCO Daily News. Today we'll be discussing key advances in GU oncology featured at the 2022 ASCO Genitourinary (GU) Cancers Symposium. I'm delighted to welcome Dr. Jason Efstathiou, who was the chair of this year's GU ASCO meeting. Dr. Efstathiou is the professor at Harvard Medical School and the director of Genitourinary Division in Radiation Oncology and clinical co-director of The Claire and John Bertucci Center for GU Cancers at the Massachusetts General Hospital. Our full disclosures are available in the show notes and the disclosure of all guests on the podcast can be found on our transcript at asco.org/podcast. Jason, thank you for coming on the podcast today.   Dr. Jason Efstathiou: Thank you very much, Neeraj. It's a real pleasure to be with you.   Dr. Neeraj Agarwal: So, Jason, the GU meeting showcased some fantastic advances across the spectrum of GU malignancies, can you please tell us about some of the hot topics that made the headlines this year?   Dr. Jason Efstathiou: Absolutely. This certainly was a dynamic and interactive hybrid ASCO GU meeting for all those attending in person, live streaming, or accessing the content on demand. With over 5,200 registrants this year, that's an actual record for this meeting and over 70 countries represented. This meeting truly serves as the premier global event for all those who diagnose, treat and study GU cancers. The meeting highlighted novel scientific and clinical findings that were high impacted. [And] in many cases will lead to practice changing care. The meeting had a real focus on diversity, global perspectives, enhanced interactivity, networking, multidisciplinary, collaborative, and evidence-based care. As you know, this year's theme was “World Class Science, Patient-Centered Care,” and this theme was highlighted throughout the program. The meeting kicked off with a rich day focusing on prostate cancer, lots on PSMA imaging, such as Abstract 9 and a very, very excellent session on PSMA targeting and beyond which explored opportunities and challenges with PSMA novel therapeutics, including biomarkers of response and mechanisms of resistance.   Then Abstract 10 looked at PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of Lutetium PSMA (177Lu-PSMA-617) vs cabazitaxel and metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. And it suggested that Lutetium PSMA be prioritized in men with high PSMA expression. And this could actually be predictive. We had some awesome abstracts. Abstracts 222 and 223 suggested that a nozzle digital pathology-based biomarker developed using artificial intelligence is more effective than clinical prognostic markers for predicting long term outcomes in patients with prostate cancer. And that this AI tool can actually successfully guide the use of androgen deprivation therapy in men with intermediate risk localized prostate cancer. And then of course, there were some very exciting results in discussion with the primary results of 3 potentially practice-changing phase 3 trials in the setting of metastatic prostate cancer that were presented in the oral prostate session. These were: PROpel (Abstract 11), MAGNITUDE (Abstract 12), and the ARASENS trials (Abstract 13). Neeraj, as a practicing medical oncologist, what did you think of these 3 abstracts?   Dr. Neeraj Agarwal: I agree with you, Jason. These are indeed practice-impacting, practice-changing abstracts, which was a record for a prostate oral session, all 3 abstracts. In fact, the results of the phase 3 trials are [likely] going to influence or impact our practice in coming months. I would like to start with Abstract 11 on the results of the PROpel trial. So, PROpel is a randomized phase 3 trial evaluating the efficacy and safety of olaparib plus abiraterone vs placebo plus abiraterone. In the first-line metastatic cast of resistant cluster cancer, docetaxel therapy was allowed for these patients if given in the metastatic castration sensitive prostate cancer setting. Enrollment in the study was independent of the defects in the homologous recombination repair gene pathway. The primary endpoint was investigator assessed radiographic progression-free survival with multiple secondary endpoints, including overall survival and safety. A total of 796 patients were randomly assigned to olaparib plus abiraterone or placebo plus abiraterone at the pre-plant interim analysis.   Results show that with a significant improvement in the radiographic progression-fee survival for all patients receiving the combination therapy, regardless of the presence of homologous recombination repair gene mutations. Overall survival analysis is still immature with only 29% event having occurred thus far. It is interesting that even patients deemed a negative for homologous recombination repair gene mutations showed significant improvement in video graphic progression-free survival when treated with the combination of olaparib plus abiraterone versus placebo plus abiraterone. I would like to mention the MAGNITUDE trial, which is Abstract 12, in the same context, as these have very similar populations and combination regimens.   So, MAGNITUDE is a randomized phase 3 trial evaluating the efficacy and safety of niraparib plus abiraterone vs placebo plus abiraterone in the first-line metastatic castrate resistant prostate cancer setting. The eligible patient population was slightly different from that in the PROpel trial—prior attacks in therapy or novel hormonal therapy in the metastatic castration sensitive prostate cancer or non-metastatic castrate resistant prostate cancer were allowed. Also, patients were eligible if they had received up to 4 months of abiraterone in the first-line metastatic CRPC setting. Prospective selection of the patients with, and without homologous recombination repair gene mutations was required.   So, the primary endpoint was radiographic progression-free survival by central with multiple secondary endpoints, including overall survival and safety. A pre-specified early fragility analysis was planned after enrolling 200 patients who are [homologous recombination repair] (HRR) negative and who were randomly assigned to receive either niraparib plus abiraterone or placebo plus abiraterone. The pre-planned fertility analysis showed no benefit in the biomarker negative cohort. Four hundred and twenty-three patients who were HRR positive were randomly assigned to receive either the combination of niraparib plus abiraterone or placebo plus niraparib at the pre-planned interim analysis. The results show that trial method—primary endpoint with a significant improvement in the radiographic progression-free survival for BRCA1 and 2 patients—and all patients who are homologous recombination repair mutation positive [were] receiving the combination of niraparib plus abiraterone versus placebo plus niraparib. Overall survival reserve is still immature.   My combined take on the PROpel and the MAGNITUDE trial, based on the data presented so far or available in the public domain so far, is that both trials establish that combination of a PARP inhibitor plus abiraterone on in the first-line settings for me, for [patients with] HRR mutation positive metastatic castration resistant prostate cancer [will] improve radiographic progression-free survival. Even though overall survival data immature for both trials, I expect both combinations will be approved by the U.S. Food and Drug Administration in the near future and will be available to our patients. The HRR negative in the PROpel trial also seemed to benefit with the combination of abiraterone plus olaparib.   I'm looking forward to data on confirmation of HRR negative status by tissue-based genomic profiling results in the full-length publication, which we expect to be published soon. If indeed confirmed, I see the combination of abiraterone plus olaparib to be reasonable option for patients who are HRR negative in the first metastatic castration prostate cancer set. The last practice changing abstract in the oral prostate session was Abstract 13 on the results of the ARASENS trial. ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide plus ADT or androgen deprivation therapy plus docetaxel versus placebo plus ADT plus docetaxel in patients with metastatic castration sensitive prostate cancer or mCSPC.   It is important to note that this study only included patients that were eligible for ADT plus docetaxel chemotherapy. The primary endpoint was overall survival with multiple secondary endpoints, including time to casted resistance, time to pain progression, time to first symptomatic skeletal event, and time to start of next antineoplastic therapy and of course, safety. A total of 1,300 patients were randomly assigned to the darolutamide plus ADT plus docetaxel vs placebo plus ADT plus docetaxel.   Results show the primary endpoint of the study was met with a significant improvement in overall survival and a 32% reduction in risk of death for patients on the triplet therapy with thalidomide plus ADT plus docetaxel. While this study offers an additional excellent option for our patients with metastatic castration sensitive prostate cancer, in an older patient population [the] use of docetaxel may be a significant limitation to this combination. In addition, this study did not answer the question [of] if adding docetaxel to ADT plus a novel hormonal therapy backbone will also improve survival with the advent of multiple doublets and triplet combinations. In the recent years, it is very important to find biomarkers which may predict response to these treatments and personalized therapy.   Dr. Jason Efstathiou: Well, Neeraj, it certainly is a mic drop moment. Isn't it? When you can announce that the New England Journal of Medicine has just released the publication of your ARASENS trial, as you're presenting it at ASCO GU don't you think (DOI: 10.1056/NEJMoa2119115)?   Dr. Neeraj Agarwal: Indeed, I think this is one of the most exciting ASCO GU meetings I've seen ever from GU ASCO. This is not an exaggeration.   Dr. Jason Efstathiou: I totally agree. It was a phenomenal meeting and a very dynamic rich prostate day.   Dr. Neeraj Agarwal: So, let's move on to the bladder cancer. Jason, what are your key takeaways from the studies of bladder cancer presented in this meet?   Dr. Jason Efstathiou: Thanks, Neeraj. Yeah, the sessions on urothelial cancer were phenomenal and there were great sessions on novel therapies, such as antibody drug conjugates in advanced urothelial cancer and management of toxicities. There were abstracts such as [Abstract] 440 suggesting that neoadjuvant gemcitabine and cisplatin produced a favorable pathologic response rate and was well tolerated in patients with high grade upper tract urothelial carcinoma, and thus should be potentially deemed a new standard. Abstract 442 was a phase 2 trial that suggested that maintenance treatment with niraparib plus best supportive care did not improve outcomes compared to best supportive care alone, in patients with advanced urothelial carcinoma that did not progress after first-line chemotherapy.   There was Abstract 435, which was an earlier face study suggesting that neoadjuvant treatment with enfortumab demonstrated promising activity among patients who are cisplatin ineligible with muscle invasive bladder cancer. And then there was a lot of focus in the meeting on trimodality therapy and optimizing bladder preservation. Dr. Alexandre R. Zlotta presented Abstract 433, which was a large multi-institutional match comparison of radical cystectomy to trimodality therapy for patients with muscle-invasive bladder cancer. And it suggested equivalent oncologic outcomes for select patients, and that trimodality therapy should be offered as an effective alternative for these patients. So Neeraj, moving on to kidney cancer, what were your key takeaways from these studies on kidney cancer presented in this meeting?   Dr. Neeraj Agarwal: Yes, Jason, thank you. There were exciting results presented from multiple studies in kidney cancer as well. For example, Abstract 290 presented by Dr. Toni K. Choueiri from the Dana-Farber Cancer Institute on the 30-month follow-up of the KEYNOTE-564, which showed continued and strong disease-free survival benefit with adjuvant pembrolizumab in the context of localized or completely dissected renal cell carcinoma. I would like to highlight that highest benefit was seen in those patients who had oligometastatic disease, who on different surgery to remove those metastatic foresight and then were randomly assigned to receive pembrolizumab vs placebo in this trial. Abstract 291, presented by Dr. Matthew Zibelman from Fox Chase Cancer Center, showed the combination of axitinib with nivolumab was associated with close to 70% objective responses. Abstract 300 on kidney cancer on more than 1,000 patients—and on the International Metastatic Renal Cell Carcinoma Consortium, or IMDC Consortium—show that in the context of first-line immunotherapy regimens, presence of lung metastasis, CT nephrectomy and better MDC risk scores correlated with improved objective responses on this novel immunotherapy regimens.   Abstract 350 on the update of the cabozantinib nivolumab was a sunitinib trial in metastatic renal cell carcinoma in the first-line setting. And it showed that the combination of cabozantinib nivolumab continues to be associated with an improved survival with the 30% reduction risk of death, even after this longer follow up—approximately 3 years. So, indeed, multiple abstracts on kidney cancer with real impact on how we practice medicine. So, Jason, let me switch gears here and talk about the education session. For example, there was a compelling keynote addressed by Dr. Karen Knudsen, the CEO of the American Cancer Society, about disparities in GU cancers in the United States. Are there any key messages that you would like to highlight briefly before we wrap up the podcast today?   Dr. Jason Efstathiou: Thanks, Neeraj. Absolutely. The educational sessions were phenomenal. There was a must-see session, by the way, on management of rare variants in GU cancers. They made management of nuanced, rare variants and rare situations, very practical. And then there was an exciting prostate focus session called “Regulating the Wild West: PET-Based Imaging in Trials and the Clinic.” This session was planned with representatives from the U.S. Food and Drug Administration as we have done for the past 3 years. But this year it looked at how often PET based imaging affects clinical decision making and prostate cancer and how the integration of novel molecular based imaging like PET informs clinical trial design and endpoints, including regulatory considerations. And yes, of course, as you noted this year's program also focused on identifying and addressing disparities in cancer care and research with sessions each day, focused on this topic (Abstract 225, 446, 472, and 26). There were great oral presentations and there was a phenomenal Virtual Poster Walk with Dr. Ahmedin Jemal from the American Cancer Society. He, by the way, is an author that we have all quoted. So, please check that out. But we were thrilled, absolutely thrilled to have Dr. Karen Knudsen, the CEO of the American Cancer Society (ACS) as our keynote speaker to address this important topic in her phenomenal and frankly, inspiring talk called “A Path Forward: Addressing Disparities in Genitourinary Cancers.” This talk was especially poignant because as you know, there is a new and robust collaboration between ASCO and the ACS that was announced earlier this month on February 1, regarding equity, diversity, and inclusion in cancer care. ASCO's work aims to address all of the important differences that can impact access to cancer care and outcomes, including age, gender, race, sexual orientation, and geography, both in the U.S. and internationally. ASCO has clearly aligned its equity, diversity, and inclusion (EDI) goals within the mission pillars of research, education, and quality.   Dr. Neeraj Agarwal: Thank you, Jason, for sharing your insights with us today. It is really an exciting time in GU oncology. Thank you.   Dr. Jason Efstathiou: Thank You, Neeraj. I totally agree.   Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you like what you're hearing on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Jason Efstathiou: Consulting or Advisory Role: Blue Earth Diagnostics, AstraZeneca, Boston Scientific, Roivant Pharma, Merck, and Myovant Sciences   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.  

Alan Cash got curious about why our energy pathways fail us. Armed with an MS in physics, he's found himself innovating commercial production methods for oxaloacetate, a metabolite in the citric acid cycle that sits squarely within our mitochondria and are fundamental in producing the ATP that fuel every energy-requiring process in the body. In this episode, we review the nitty gritty details of energy production from the perspective of how oxaloacetate (brand names Benagene and Jubilance) can impact us from the systemic perspective. We don't typically discuss one commercial product on our show, but we have many patients using oxaloacetate and wanted to give a much more complete picture than we can in a clinic visit. Taking oxaloacetate has been shown to decrease NF-kB activation, reduce fasting glucose by ~25% (research from the late 1960's), increase NAD to NADH ratios, increase AMPK, decrease emotional symptoms of PMS (as the product Jubilance) and favorably shift cellular redox. Preliminary data from Mr Cash's current research is showing reduction in fatigue for CFS/ME patients. Remarkably, oral oxaloacetate seems to be able to cross the blood brain barrier (it's a very small molecule!) and can decrease brain glutamate levels. Most remarkably, taking exogenous oxaloacetate can mimic caloric restriction and has increased the lifespan of laboratory animals. It's been used in doses ranging from 100 to 6000mg daily (like for glioblastoma) and has been well-tolerated even at high doses. It's important to know that the commercial products Benagene and Jubilance contain the same ingredients: 100mg of oxaloacetate stabilized by 150mg of vitamin C. To answer another common question, there's no mechanism to turn oxaloacetate into the undesirable 'oxalate' compound in the human body. This tiny molecule really can pack a molecular and anti-inflammatory punch- listen in to find out more! Resources: https://benagene.com/ https://jubilance.com/ Oxaloacetate to reduce emotional symptoms in PMS: placebo-controlled, cross-over clinical trial with 48 women (2020): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073356/ Safety and target engagement profile of two oxaloacetate doses (500mg & 1000mg twice daily) in 15 Alzheimer's patients (2021) showed the higher dose increased frontal & frontoparietal brain glucose & glutathione per FDG PET scanning despite no changes in serum levels or cognitive scoring. https://pubmed.ncbi.nlm.nih.gov/32715609/ Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation & stimulates neurogenesis (2014) in mice injected with 1-2g/kg once daily dosing x 1-2 weeks. https://pubmed.ncbi.nlm.nih.gov/25027327/ Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans (roundworms) by 25% median & 13% maximal lifespan through an AMPK/FOXO-dependent pathway (2009). https://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2009.00527.x Oxaloacetate: A novel neuroprotective for acute ischemic stroke (2012) via modulation of the glutamate pathway which would also be applicable for other types of brain injury, like TBI (traumatic brain injury). https://pubmed.ncbi.nlm.nih.gov/22085530/ Neuroprotective effect of oxaloacetate in a focal brain ischemic model in the rat (2015) through pathways of glutamate scavenging. https://pubmed.ncbi.nlm.nih.gov/24807461/ Neuroprotective effects of oxaloacetate in closed head injury in rats is mediated by its blood glutatmate scavenging activity (2009). https://pubmed.ncbi.nlm.nih.gov/19543002/ Effect of alpha-ketoglutarate & oxaloacetate on brain mito DNA damage & seizures (2003). https://pubmed.ncbi.nlm.nih.gov/12749815/ Oxaloacetate acid supplementation as a mimic of caloric restriction: https://benthamopen.com/contents/pdf/TOLSJ/TOLSJ-3-22.pdf

 Image of the Year Ganna Blazhenets FDG 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... [[ This is a content summary only. Visit my website for full links, other content, and more! ]]

Dr. Ahmed Tawakol, MD, Co-Director, Cardiac MR PET CT Program at Massachusetts General Hospital discusses his recent research, "Alcohol's Beneficial Effect on Cardiovascular Disease is Partially Mediated Through Modulation of Stress Associated Brain Activity". The study, which was presented at the 2021 American College of Cardiology's annual scientific meeting, seeks to understand how alcohol plays a role in major adverse cardiovascular events. #ACC21 Dr Tawakol graduated from Stanford Medical School and did his Medical Residency and Cardiovascular Diseases Fellowship at Brigham and Women's Hospital. He subsequently completed training in Nuclear Cardiology at Massachusetts General Hospital, after which he joined the Cardiology Division staff. His clinical focus is in nuclear cardiology and general cardiology, with a special focus on the identification of patients at highest risk for atherothrombotic event. Dr Tawakol's research interest is in imaging of atherosclerosis. His work has focused on developing novel diagnostic approaches and novel treatment strategies for atherosclerosis. To that end, Dr Tawakol has developed and validated molecular methods to characterize atherosclerotic plaques, and has made seminal observations validating the use of FDG-PET imaging for the measurement of atherosclerotic plaque inflammation. Currently, he is leading several multi-center trials to evaluate interventions targeting plaque inflammation and is evaluating the potential clinical role of vascular PET imaging for improving the identification of patients at highest risk for atherothrombotic events.

This Podcast is for educational purposes only not intended to treat cure diagnose or prevent sickness illness disease or mental health issues if you are making any lifestyle changes to your health and wellness routine for yourself and family consult with your medical doctor first. Reference Richardson, M. A., Sanders, T., Palmer, J. L., Greisinger, A., & Singletary, S. E. (2000). Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. Journal of Clinical Oncology, 18(13), 2505-2514 Mikhaeel, N. G., Timothy, A. R., O'Doherty, M. J., Hain, S., & Maisey, M. N. (2000). 18-FDG-PET as a prognostic indicator in the treatment of aggressive Non-Hodgkin's Lymphoma-comparison with CT. Leukemia & lymphoma, 39(5-6), 543-553 Armitage, J. O., & Weisenburger, D. D. (1998). New approach to classifying non-Hodgkin's lymphomas: clinical feature . #herbs #NonHodgkinLymphoma #Cancer #Cancertreatments #wellness #selfcare #alternativehealth #holistichealth #holisticherbaltreatment #holisticeducation --- Send in a voice message: https://anchor.fm/rdlc/message Support this podcast: https://anchor.fm/rdlc/support

A natural food supplement may relieve anxiety Weizmann Institute of Science, May 24, 2021 A natural food supplement reduces anxiety in mice, according to a new Weizmann Institute of Science study. The plant-derived substance, beta-sitosterol, was found to produce this effect both on its own and in synergic combination with an antidepressant known under the brand name Prozac. If these findings, published today in Cell Reports Medicine, are confirmed in clinical trials, they could point the way toward the use of beta-sitosterol as a treatment for relieving anxiety in humans. Anxiety is not always a bad thing. In fact, in evolutionary terms, feeling anxious about potential threats is critical for survival because it helps us mount an appropriate response. That's precisely why developing antianxiety drugs is so challenging. The circuits for anxiety in the brain are closely related to those responsible for memory, awareness and other functions vital for handling danger, so scientists are on the lookout for compounds that can selectively suppress anxiety without causing unwanted side effects. The starting point for the present study was research conducted several years ago in the lab of Prof. Mike Fainzilber in Weizmann's Biomolecular Sciences Department. Dr. Nicolas Panayotis and other lab members studied the roles of proteins that shuttle cargoes into the nuclei of nerve cells, and they discovered that in stressful situations, mice lacking a shuttling protein known as importin alpha-five showed less anxiety than the control mice. The researchers then checked how these 'calmer' mice differed from regular ones in terms of gene expression, and they identified a genetic signature of their calmness: about 120 genes with a characteristic pattern of expression in the hippocampus, one of the brain regions that regulate anxiety. In the new study, Panayotis, now a senior intern in Fainzilber's lab, together with colleagues, searched an international genomic database for existing drugs or other compounds that might mimic the same gene expression signature. He identified five candidates and tested their effects on behavior in mice. That was how the researchers zeroed in on beta-sitosterol, a plant substance sold as a dietary supplement intended mainly to reduce cholesterol levels. In a series of behavioral experiments, mice given beta-sitosterol showed much less anxiety than the controls. They were, for example, less fearful than the controls when placed in an illuminated enclosure, daring to walk into its brightly lit center, whereas regular mice were careful to stay on the darker periphery, avoiding the stress of the bright light. Moreover, the mice receiving beta-sitosterol did not exhibit any of the side effects that might be expected from antianxiety medications—their locomotion was not impaired, and they did not refrain from exploring novel stimuli. Next, the researchers tested the effects of beta-sitosterol on mice when given in combination with fluoxetine, a drug belonging to the class of selective serotonin reuptake inhibitors, or SSRIs, and sold under the brand name Prozac, among others. The combination had a synergistic effect: Both beta-sitosterol and fluoxetine reduced the anxiety of mice at lower doses when given together, compared with the doses needed to produce the same effect when they were administered separately. "One of the major problems with existing antianxiety medications is that they produce side effects, so if beta-sitosterol could help cut down the dosage of such medications, it might potentially also reduce the unwanted side effects," Panayotis says. A great advantage of beta-sitosterol is that it is naturally present in a variety of edible plants, and it is thought to be safe, as it has been marketed for years as a nutraceutical. It is found in particularly large concentrations in avocados, but also in pistachios, almonds and other nuts, in canola oil, in various grains and cereals and more. However, this does not mean that eating avocado can induce a calming effect, since it doesn't contain enough beta-sitosterol. "You'd need to eat avocado day and night to get the right dose—and you would be more likely to develop digestive problems than relieve your anxiety," Panayotis says. The precise mechanism of beta-sitosterol's effect on anxiety remains to be revealed, but the scientists did find that the expression of several genes known to be activated in stressful situations was reduced in mice given the supplement. They also found that these mice had changes in the levels of certain metabolites and neurotransmitters in brain areas involved in anxiety. Since the study focused on brain regions and neural pathways that are involved in regulating anxiety in both mice and humans, it is likely that the findings will apply to humans as well. This will, however, require further clinical testing. As Fainzilber points out: "There's a need for a clinical trial to test the use of beta-sitosterol for reducing anxiety in humans. Until then, we recommend that people consult their physicians before taking the supplement for this purpose."   Benfotiamine, vitamin B derivative, intake associated with reduced progression of cognitive decline Weil Cornell Medicine, May 20, 2021 A randomized phase II trial reported in 2020 in the Journal of Alzheimer’s Disease resulted in positive effects among individuals with amnestic mild cognitive impairment or mild Alzheimer’s dementia who were given capsules that contained benfotiamine, a derivative of thiamine (vitamin B1).  The trial included 70 cognitively impaired men and women who received physical examinations and completed the Mini-Mental Status Exam (MMSE) prior to enrollment. Prospective candidates received positron emission tomography (PET)/CT scans of the brain to confirm the presence of amyloid plaques that are characteristic of Alzheimer disease) and other general blood tests, an electrocardiogram and neurological exam prior to enrollment. Screening tests commonly used to test for diabetes were also performed prior to enrollment, and participants were required to have a hemoglobin A1c (HbA1c) of less than 8% and/or a fasting glucose of less than 200 milligrams per deciliter to be enrolled in the trial. APOE genotype was determined upon enrollment in the trial. The presence of one or two copies of the APOE4 variant of the APOE gene is associated with a greater risk of Alzheimer disease in comparison with APOE2 or APOE3. Blood testing conducted at the beginning and end of the trial measured levels of vitamin B1 and advanced glycation end-products (AGEs), which are formed when fats or proteins react with sugar in the blood. (Research suggests that AGEs are predictive of long-term decline in cognition-related daily living performance in Alzheimer disease patients.) Participants also underwent fluorodeoxyglucose positron-emission tomography (FDG PET) at these time points to assess brain glucose utilization which, when reduced, is associated with cognitive decline. Cognitive tests, including the Alzheimer Disease Assessment Scale-Cognitive Subscale, Clinical Dementia Rating and others were administered at the beginning of the study and at varying time points thereafter. Participants received capsules containing 300 milligrams benfotiamine or a placebo twice daily for one year.  At the end of the treatment period, thiamine levels were significantly elevated in the benfotiamine-intake group. The 12 month increase in Alzheimer Disease Assessment Scale-Cognitive Subscale scores (indicating increased cognitive dysfunction) was lower among those who received benfotiamine compared to the placebo group. Benfotiamine intake participants additionally experienced 77% less deterioration in Clinical Dementia Rating scores compared to the placebo group; however, the effect seen with benfotiamine was stronger among participants who did not have the APOE4 variant. Benfotiamine was also associated with a significant reduction in the increase in AGEs compared to the placebo, which again was stronger in noncarriers of APOE4. FDG PET data suggested that participants without APOE4 were more responsive to benfotiamine intake. “Benfotiamine is safe and cost effective, and the results of this pilot study are encouraging, providing preliminary evidence of efficacy,” authors Gary E. Gibson of Weil Cornell Medicine and colleagues concluded. “Our next step is to propose a larger clinical trial appropriately powered to replicate our findings. We believe that further studies would be very valuable to determine whether benfotiamine may be helpful in delaying onset or treating Alzheimer disease.”   '45 is the new 50' as age for colorectal cancer screening is lowered Dana Farber Cancer Institute, May 21, 2021 BOSTON - Prompted by a recent alarming rise in cases of colorectal cancer in people younger than 50, an independent expert panel has recommended that individuals of average risk for the disease begin screening exams at 45 years of age instead of the traditional 50.  The guideline changes by the U.S. Preventive Services Task Force (USPSTF), published in the current issue of JAMA, updates its 2016 recommendations and aligns them with those of the American Cancer Society, which lowered the age for initiation of screening to 45 years in 2018. Colorectal cancer (CRC) is one of the most preventable malignancies, owing to its long natural history of progression and the availability of screening tests that can intercept and detect the disease early. Overall incidence of CRC in individuals 50 years of age and older has declined steadily since the mid-1980s, largely because of increased screening and changing patterns of modifiable risk factors. "A concerning increase in colorectal cancer incidence among younger individuals (ie, younger than 50 years; defined as young-onset colorectal cancer) has been documented since the mid-1990s, with 11% of colon cancers and 15% of rectal cancers in 2020 occurring among patients younger than 50 years, compared with 5% and 9%, respectively, in 2010," said Kimmie Ng, MD, MPH, first author of an editorial in JAMA accompanying the article about the guideline change of the USPSTF. Ng is the director of the Young-Onset Colorectal Cancer Center at Dana-Farber Cancer Institute.  The causes of the increase in young-onset CRC aren't currently known.  Lowering the recommended age to initiate screening "will make colorectal cancer screening, which is so important, available to millions more people in the United States, and hopefully many more lives will be saved by catching colorectal cancer earlier, as well as by preventing colorectal cancer," said Ng. The USPSTF is an independent panel of experts funded by the U.S. Department of Health and Human Services. It systematically reviews the evidence of effectiveness of preventive services and develops recommendations. American health insurance groups are required to cover, at no charge to the patient, any service that the USPSTF recommends with a grade A or B level of evidence, regardless of how much it costs. The task force recommendation means that insurers will be required to cover preventive procedures such as colonoscopies and stool tests designed to detect colon cancer in early stages. The task force selected age 45 based on research showing that initiating screening at that age averted more early deaths than starting at age 50, with a relatively small increase in the number of colonoscopy complications. There is no change to the USPSTF 2016 recommendation to only selectively screen individuals aged 76 to 85, as research shows only small increases in life-years gained. The accompanying JAMA editorial asked rhetorically whether the age of screening should be lowered even younger than age 45. While the majority of young-onset CRC diagnoses and deaths occurs in persons 45 to 49, the rate of increase in young-onset CRC is actually steepest in the very youngest patients. Colon cancer incidence is increasing by 2% per year in 20 to 29-year-olds, compared with 1.3% in 40 to 49-year-olds. Rectal cancer incidence is increasing by 3.2% per year in 20 to 29-year-olds and 30 to 39-year-olds, versus 2.3% in 40 to 49-year-olds. "We are now seeing patients even younger than 45 - in their 20s and 30s - who are being diagnosed with this cancer and often at very late stages," said Ng. "Clearly the USPSTF recommendation to start screening at age 45 will not be enough to catch those young people who are being diagnosed." Ultimately, optimal prevention and early detection of CRC in people younger than 45 will require further research into the underlying causes and risk factors of young-onset CRC, which have thus far remained elusive, said the editorial authors.  The authors also called for "bold steps" to translate the lowered age of beginning screening into meaningful decreases in CRC incidence and mortality, noting that despite the preventive benefits of colorectal cancer screening, only 68.8 percent of eligible individuals in the United States undergo screening. The rate is lower among the uninsured and underinsured, those with low incomes, and racial and ethnic minorities. Barriers include lack of knowledge of the importance of screening, concerns about the invasive nature of colonoscopy, and lack of access to and provider recommendations for screening. The editorial lists examples including public awareness campaigns, including those aimed at gaps in CRC incidence and mortality between Black and white Americans, and specific actions. Employers could provide 45-year-old employees with a paid "wellness day" to undergo CRC screening, or offer day care or transportation vouchers to overcome the logistical hurdles of colonoscopies. Health systems could offer weekend or after-hours appointments for colonoscopies. The new recommendation "represents an important policy change," the authors wrote, "to drive progress toward reducing colorectal cancer incidence and mortality."     Study Finds New and Effective Treatment for Vitamin D Deficiency Boston University School of Medicine, May 20, 2021 There are several million people worldwide with various fat malabsorption syndromes including those who have undergone gastric bypass surgery and those with obesity. These patients often have a difficult time absorbing vitamin D and both groups of patients are at an increased risk for vitamin D deficiency and therefore at higher risk for osteoporosis and osteomalacia (softening of the bones). Patients with obesity are also susceptible to vitamin D deficiency as vitamin D derived from intestinal absorption and cutaneous synthesis is diluted in a larger body pool of fat. Now a new study demonstrates 25-hydroxyvitamin D3 is an effective treatment for vitamin D deficiency for these specific patients. According to the researchers, approximately one third of adults are obese and require much larger doses of vitamin D to satisfy their requirement. "This vitamin D metabolite is better absorbed in patients with fat malabsorption syndromes and since it is not as fat soluble, it does not gets diluted in the body fat and is effective in raising and maintaining blood levels of 25-hydroxyvitamin D in obese people," explained corresponding author Michael F. Holick, PhD, MD, professor of medicine, physiology and biophysics and molecular medicine at Boston University School of Medicine. Healthy adults, adults with a fat malabsorption syndrome and obese adults were compared to evaluate if a more water-soluble form of vitamin D3 known as 25-hydroxyvitamin D3 was more effective than the same dose of vitamin D3 in improving their vitamin D status. The researchers observed that compared to healthy adults only about 36 percent of orally ingested vitamin D3 was found in the blood of patients with fat malabsorption syndromes including patients who had gastric bypass surgery. When the same adults ingested 25-hydroxyvitamin D3 the patients with fat malabsorption syndromes were able to absorb it as well as the healthy adults thereby raising their vitamin D status to the same degree. A similar observation was made in the obese subjects compared to the healthy controls. "Therefore using 25-hydroxyvitamin D3 could be a novel approach for treating vitamin D deficiency in patients with fat malabsorption syndromes and obese adults," added Holick. Vitamin D deficiency not only results in bone loss increasing risk for fracture but causes the painful bone disease osteomalacia. Patients who are vitamin D deficient with osteomalacia have unrelenting achiness in their bones and muscles. Vitamin D deficiency has been associated with an increased risk of many chronic illnesses including multiple sclerosis, type 1 diabetes, heart disease, type 2 diabetes, depression, neurocognitive dysfunction and Alzheimer's disease as well as infectious diseases including COVID. These findings appear online in the American Journal of Clinical Nutrition.   Young teens should only use recreational internet and video games one hour daily Rutgers University, May 24, 2021 Middle-school aged children who use the internet, social media or video games recreationally for more than an hour each day during the school week have significantly lower grades and test scores, according to a study from the Center for Gambling Studies at Rutgers University-New Brunswick. The findings appear in the journal Computers in Human Behavior.  Researchers say the findings give parents and children a moderate threshold for using entertainment-related technology -- no more than one hour daily on school days and four hours a day on weekends.  "Interactive technology is widely used to promote children's educational access and achievement," said lead author Vivien (Wen Li) Anthony, an assistant professor at the School of Social Work and research associate at the Rutgers Center for Gambling Studies. "During the COVID-19 pandemic, technology has been essential to facilitating remote learning. At the same time, there is a growing concern that excessive technology use, particularly for entertainment, may adversely affect children's educational development by facilitating undesirable study habits and detracting from time spent on learning activities."  The researchers, which include Professor Lia Nower of the Rutgers Center for Gambling Studies and a researcher from Renmin University of China, analyzed the China Education Panel Survey data, a national survey of educational needs and outcomes of children in China. Approximately 10,000 first-year middle school students were surveyed and followed. Their average age was 13.5 years. The results showed that children who used the internet, social media or video games for entertainment four or more hours daily were four times more likely to skip school than those who did not. Boys used interactive technology for entertainment significantly more than girls. Boys also performed worse and showed lower school engagement levels than girls. "Such findings are critical, particularly in light of the recent movement toward online learning in countries throughout the world," said Anthony. "In a learning environment that integrates the internet, it is easy for children to move across educational and entertainment platforms during learning without alerting teachers or adults to alternate activities." Anthony said children in the study who used technology in moderation (i.e., less than one hour per day on weekends) experienced less boredom at school, potentially due to the positive effects of participation in social media, video games and video streaming such as peer bonding and relationship building. Using interactive technology for entertainment in moderation advanced children's cognitive development.  The findings suggest that parents place time limits on their children's interactive technology use, and that parents and teachers should help children to develop effective time management and self-regulation skills to reduce their reliance on technology.   Do people aged 105 and over live longer because they have more efficient DNA repair? University of Bologna (Italy),  May 19, 2021 Researchers have found that people who live beyond 105 years tend to have a unique genetic background that makes their bodies more efficient at repairing DNA, according to a study published in eLife. This is the first time that people with ‘extreme longevity’ have had their genomes decoded in such detail, providing clues as to why they live so long and manage to avoid age-related diseases. “Aging is a common risk factor for several chronic diseases and conditions,” explains Paolo Garagnani, Associate Professor at the Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy, and a first author of the study. “We chose to study the genetics of a group of people who lived beyond 105 years old and compare them with a group of younger adults from the same area in Italy, as people in this younger age group tend to avoid many age-related diseases and therefore represent the best example of healthy aging.” Garagnani and colleagues, in collaboration with several research groups in Italy and a research team led by Patrick Descombes at Nestle Research in Lausanne, Switzerland, recruited 81 semi-supercentenarians (those aged 105 years or older) and supercentenarians (those aged 110 years or older) from across the Italian peninsula. They compared these with 36 healthy people matched from the same region who were an average age of 68 years old. They took blood samples from all the participants and conducted whole-genome sequencing to look for differences in the genes between the older and younger group. They then cross-checked their new results with genetic data from another previously published study which analysed 333 Italian people aged over 100 years old and 358 people aged around 60 years old. They identified five common genetic changes that were more frequent in the 105+/110+ age groups, between two genes called COA1 and STK17A. When they cross-checked this against the published data, they found the same variants in the people aged over 100. Data acquired from computational analyses predicted that this genetic variability likely modulates the expression of three different genes. The most frequently seen genetic changes were linked to increased activity of the STK17A gene in some tissues. This gene is involved in three areas important to the health of cells: coordinating the cell’s response to DNA damage, encouraging damaged cells to undergo programmed cell death and managing the amount of dangerous reactive oxygen species within a cell. These are important processes involved in the initiation and growth of many diseases such as cancer. The most frequent genetic changes are also linked to reduced activity of the COA1 gene in some tissues. This gene is known to be important for the proper crosstalk between the cell nucleus and mitochondria - the energy-production factories in our cells whose dysfunction is a key factor in aging. Additionally, the same region of the genome is linked to an increased expression of BLVRA in some tissues - a gene that is important to the health of cells due to its role in eliminating dangerous reactive oxygen species. “Previous studies showed that DNA repair is one of the mechanisms allowing an extended lifespan across species,” says Cristina Giuliani, Senior Assistant Professor at the Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, University of Bologna, and a senior author of the study. “We showed that this is true also within humans, and data suggest that the natural diversity in people reaching the last decades of life are, in part, linked to genetic variability that gives semi-supercentenarians the peculiar capability of efficiently managing cellular damage during their life course.” The team also measured the number of naturally occurring mutations that people in each age group had accumulated throughout their life. They found that people aged 105+ or 110+ had a much lower burden of mutations in six out of seven genes tested. These individuals appeared to avoid the age-related increase in disruptive mutations, and this may have contributed in protecting them against diseases such as heart disease. “This study constitutes the first whole-genome sequencing of extreme longevity at high coverage that allowed us to look at both inherited and naturally occurring genetic changes in older people,” says Massimo Delledonne, Full Professor at the University of Verona and a first author of the study. “Our results suggest that DNA repair mechanisms and a low burden of mutations in specific genes are two central mechanisms that have protected people who have reached extreme longevity from age-related diseases,” concludes senior author Claudio Franceschi, Professor Emeritus of Immunology at the University of Bologna.       Your Risk of Dying Hinges on Well-Being Not Diseases     University of Chicago, May 18, 2021 A new study has yielded a radically different picture of aging in America, finding that how old you are plays little or no role in determining differences in health and well-being. The researchers say the results suggest the medical community is focusing on the wrong set of factors to determine risk of dying. Rather than rely on a checklist of infirmities—heart disease, cancer, diabetes, high blood pressure, and cholesterol levels—perhaps it’s time to consider a new “comprehensive model” that looks at factors such as psychological well-being, sensory function, and mobility. “The new comprehensive model of health identifies constellations of health completely hidden by the medical model and reclassifies about half of the people seen as healthy as having significant vulnerabilities that affect the chances that they may die or become incapacitated within five years,” says Professor Martha McClintock, a biopsychologist and lead author of the study in the Proceedings of the National Academy of Sciences. “At the same time, some people with chronic disease are revealed as having many strengths that lead to their reclassification as quite healthy, with low risks of death and incapacity,” adds Professor Linda Waite, a demographer and study coauthor. The study is a major longitudinal survey of a representative sample of 3,000 people between the ages of 57 to 85 conducted by the independent research organization NORC at the University of Chicago. SOME OF THE FINDINGS INCLUDE: Cancer itself is not related to other conditions that undermine health. Poor mental health, which afflicts one in eight older adults, undermines healthin ways not previously recognized. Obesity seems to pose little risk to older adults with excellent physical and mental health. Sensory function and social participation play critical roles in sustaining or undermining health. Breaking a bone after age 45 is a major marker for future healthissues. Older men and women have different patterns of healthand well-being during aging. Mobility is one of the best markers of well-being. The comprehensive model reflects a definition of health long advanced, but little studied, by the World Health Organization, which considers health to include psychological, social, and physical factors in addition to the diseases that are the basis for the current medical model of health. THE HEALTHIEST 22% Twenty-two percent of older Americans were in the model’s healthiest category. This group was typified by higher obesity and blood pressure, but had fewer organ system diseases, better mobility, sensory function, and psychological health. They had the lowest prevalence of dying or becoming incapacitated (six percent) five years into the study. A second category had normal weight, low prevalence of cardiovascular disease and diabetes, but had one minor disease such as thyroid disease, peptic ulcers, or anemia. They were twice as likely to have died or become incapacitated within five years. Two emerging vulnerable classes of health traits, completely overlooked by the medical model, included 28 percent of the older population. One group included people who had broken a bone after age 45. A second new class had mental health problems, in addition to poor sleep patterns, engaged in heavy drinking, had a poor sense of smell, and walked slowly, all of which correlate with depression. The most vulnerable older people were in two classes—one characterized by immobility and uncontrolled diabetes and hypertension. A majority of people in each of these categories were women, who tend to outlive men. “From a health system perspective, a shift of attention is needed from disease-focused management, such as medications for hypertension or high cholesterol, to overall well-being across many areas,” says William Dale, associate professor of medicine and a member of the research team. “Instead of policies focused on reducing obesity as a much lamented health condition, greater support for reducing loneliness among isolated older adults or restoring sensory functions would be more effective in enhancing health and well-being in the older population,” says Edward Laumann, also a collaborator and sociology professor.

How can cancer and cancer cells be understood through the lens of cellular metabolism, and what insights can be gained into various forms of treatment? Many studies suggest that metabolic changes and the environment in which the cells inhabit can significantly impact how they function. Listen in to learn: How cancer cells are affected by oxygen availability Some often-overlooked benefits of Chemotherapy How cellular metabolism and pathways can affect the development of cancer cells Oncologist and cancer researcher at the Koch Institute at MIT, Dr. Matthew Vander Heiden, shares his research experience and some surprising cellular processes that can dramatically impact cancer cells. Dr. Vander Heiden sheds light on the Warburg effect, which describes how cancer cells tend to uptake glucose and ferment it rather than burning it in respiration. The fermentation of glucose rather than respiration is revealed to be how FDG PET scans function by differentiating cancer cells that use more sugar and show up highlighted on the scan. The fermentation process ultimately produces ATP and lactate to fuel the cancer cell. Alongside development pathways for the cells, oxygen is also a limiting factor on cancer cells, and the lack or surplus will encourage particular pathways to be used. Due to the availability of particular nutrients in different regions of the body, it is also thought that an individual's diet can impact the development of cancer cells. This is explained the clustering and absorption of those nutrients at different concentrations throughout the body. For more information, visit https://ki.mit.edu. Episode also available on Apple Podcasts: apple.co/30PvU9C

The latest in cancer therapeutics is just around the corner. Press play to learn from a true expert in the field and discover: How immune checkpoint inhibitors work What can be learned from the triangular communication that occurs between a primary tumor, metastatic site, and bone marrow When new and unprecedented therapeutics for cancer may be commercially available Dr. Doru Paul is Associate Professor of Clinical Medicine at Weill Cornell Medical College, a practicing oncologist and hematologist who has treated more than 10,000 patients with various types of cancers over the years, and a clinical and translational researcher who has been involved with over 30 studies in oncology. He also works within the realm of theoretical biology, all with the goal of better understanding cancer and finding more effective, less toxic ways to treat it. Dr. Paul has only been practicing at Cornell for the past three years, but he's been at the cancer riddle for more than 33 years now. While at Cornell, he has focused on the treatment of head and neck cancers, some of the most common being throat, nasopharynx, and thyroid cancer. In today's show, he explains the recent success with immunotherapy, both by itself and in combination with chemotherapy, as well as some of the newest medications being used, like monoclonal antibody (MAB) immune checkpoint inhibitors. He discusses the use of FDG-PET (fluorodeoxyglucose-positron emission tomography) to attack cancer vulnerabilities, dispels some of the misconceptions surrounding this approach, and explains why it's actually effective and free of side effects. He also discusses an idea that he's been developing over the past six years, which requires zooming out from the microscopic level to the macroscopic level and focusing on the killer of 90 percent of patients: metastasis. Specifically, he talks about the communication that occurs between primary tumors, metastatic sites, and bone marrow, and targeted approaches that function at this level. Tune in for details on these topics and more. Episode also available on Apple Podcasts: apple.co/30PvU9C

CardioNerd Amit Goyal is joined by Dr. Erika Hutt (Cleveland Clinic general cardiology fellow), Dr. Aldo Schenone (Brigham and Women’s advanced cardiovascular imaging fellow), and Dr. Wael Jaber (Cleveland Clinic cardiovascular imaging staff and co-founder of Cardiac Imaging Agora) to discuss nuclear and complimentary multimodality cardiovascular imaging for the evaluation of myocardial viability. Show notes were created by Dr. Hussain Khalid (University of Florida general cardiology fellow and CardioNerds Academy fellow in House Thomas). To learn more about multimodality cardiovascular imaging, check out Cardiac Imaging Agora!  Collect free to CME/MOC credit just for listening to the episode!  CardioNerds Multimodality Cardiovascular Imaging PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show Notes & Take Home Pearls In response to ischemia the myocardium can dynamically change along a spectrum from myocardial stunning to myocardial hibernation to myocardial necrosis. The goals of viability testing are to identify patients who may benefit from revascularization as hibernating or stunned myocardium are potentially reversible causes of LV dysfunction. There are numerous imaging modalities available for the evaluation of myocardial viability. The broad range of ways in which myocardial viability is assessed speaks to the complexity of the disease spectrum and the difficulty in creating a unifying definition of viability to assess in clinical trials.   Five Take Home Pearls 1. In response to an acute episode of ischemia with subsequent reperfusion, the myocardium can be exposed to a large flux of oxygen free radicals or calcium overload that affects the cellular membrane and contractile apparatus. This phenotypically results in decreased contractility of the affected region of myocardium that can persist for weeks, labeled myocardial stunning  2. Repeated episodes of myocardial stunning or chronic low myocardial blood flow can lead to cellular changes such as resorption of the contractile apparatus in order to decrease oxygen demand and allow the myocardial cells to survive. Phenotypically, this might appear as regions of hypokinesis or akinesis at rest with a fixed perfusion defect on myocardial perfusion imaging. This is typically considered hibernating myocardium.   3. The goal of myocardial viability testing is to be able to differentiate between stunned, hibernating and necrosed myocardium. In patients with known epicardial coronary disease, this differentiation allows us to identify who may benefit from revascularization with improved LV systolic function and overall survival.   4. There are several imaging modalities that can be used in the assessment of myocardial viability. The most sensitive modalities are FDG-PET and CMR. The addition of Dobutamine or first pass perfusion with Gadolinium additionally increases the specificity of CMR. These modalities are more expensive and not as widely available.   5. The dynamic nature of the myocardial hibernation and the lack of a unifying definition/phenotypic expression of myocardial hibernation and viability have made it difficult for clinical trials to show that re-establishing myocardial blood flow to hibernating myocardium is beneficial. As Dr. Jaber stated in the episode in his spin on the classic opening phrase from Leo Tolstoy’s masterpiece, Anna Karenina, “All normal hearts are normal in the same way, and all abnormal hearts are abnormal in different ways.”  6. The PARR-2 trial was one of the few randomized, controlled trials of patients with LV systolic dysfunction and coronary artery disease who were randomized to either FDG-PET guided management or standard care with respect to whether to pursue revascularization. Overall,

This shorter episode on metabolic changes and hemodynamics covers a wide range of neuroimaging techniques, including FDG PET, MRI and CT. Judy will discuss the applications of these modalities in deep learning, AD diagnosis and more. Definitely worth a listen if you're into neuroimaging!   Sections in this episode:  FTG PET papers - 1:02  MRI papers - 9:40 ------------------------------------------------------------------  To receive the list of papers covered, please fill this form:  -------->  https://forms.gle/CVVbznAFM8pamdgk6  -------  or by tweeting at us: @AMiNDR_podcast  ------------------------------------------------------------------ We would appreciate your feedback so we can better cater to your needs.  You can fill our feedback form here  ---------->  https://forms.gle/5aq2JyrT6g4P1m8v6  You can also share your thoughts and suggestions by contacting us:  Email: amindrpodcast@gmail.com  Facebook:  AMiNDR  Twitter: @AMiNDR_podcastInstagram: @AMiNDR.podcast------------------------------------------------------------------ Today's episode was scripted and hosted by Judy Cheng, and edited by Anusha Kamesh. Big thanks to Elyn Rowe and Jacques Ferreira for sorting all the papers published in September into themes for our episodes, and props to the team that works very hard behind the scenes to make all this possible. Our music is from "Journey of a Neurotransmitter" by musician and fellow neuroscientist Anusha Kamesh; you can find the original piece and her other music on soundcloud under Anusha Kamesh or on her YouTube channel, AKMusic.   https://www.youtube.com/channel/UCMH7chrAdtCUZuGia16FR4w   ------------------------------------------------------------------ If you are interested in joining the team, send us your CV by email. We are specifically looking for help with abstract summary and podcast editing. However, if you are interested in helping in other ways, don't hesitate to apply anyways.  ------------------------------------------------------------------ *About AMiNDR: *  Learn more about this project and the team behind it by listening to our first episode: "Welcome to AMiNDR!" 

Full article: https://www.ajronline.org/doi/abs/10.2214/AJR.20.24567  Patients with borderline resectable and locally advanced pancreatic cancer receiving neoadjuvant therapy can have results comparable to patients with resectable tumor at presentation, however some patients have early recurrence after neoadjuvant therapy and resection. Jordan Perchik, MD discusses a new AJR study in which a team of radiologists evaluate multiple imaging parameters and tumor metrics to assess for characteristics to predict pathologic response prior to resection.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.19.258236v1?rss=1 Authors: Stojakovic, A., Chang, S.-Y., Nesbitt, J., Pichurin, N. P., Ostroot, M., Trushina, E. Abstract: Background: Accumulation of hyperphosphorylated Tau (pTau) protein is associated with synaptic dysfunction in Alzheimers disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on pTau levels, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5 - 18 months of age. Cognitive function was assessed using the Morris water maze test. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity and cognitive function, increased levels of synaptic proteins, improved glucose metabolism and energy homeostasis in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3{beta} (GSK3{beta}). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for AD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.13.200519v1?rss=1 Authors: Meinhardt, M. W., Pfarr, S., Rohleder, C., Vengeliene, V., Barroso-Flores, J., Hoffmann, R., Meinhardt, M. L., Paul, E., Hansson, A. C., Köhr, G., Meier, N., von Bohlen und Halbach, O., Bell, R. L., Endepols, H., Neumaier, B., Schönig, K., Bartsch, D., Spanagel, R., Sommer, W. H. Abstract: Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.01.182428v1?rss=1 Authors: Stojakovic, A., Trushin, S., Sheu, A., Khalili, L., Chang, S.-Y., Li, X., Christensen, T., Salisbury, J. L., Geroux, R. E., Gateno, B., Flannery, P. J., Dehankar, M., Funk, C. C., Wilkins, J., Stepanova, A., OHagan, T., Galkin, A., Nesbitt, J., Zhu, X., Tripathi, U., Macura, S., Tchkonia, T., Pirtskhalava, T., Kirkland, J. L., Kudgus, R. A., Schoon, R. A., Reid, J. M., Yamazaki, Y., Kanekiyo, T., Zhang, S., Nemutlu, E., Dzeja, P., Jaspersen, A., Kwon, C. Y. I., Lee, M. K., Trushina, E. Abstract: We demonstrate that mitochondrial respiratory chain complex I is an important small molecule druggable target in Alzheimers Disease (AD). Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 mice, a translational model of AD. Treatment of APP/PS1 mice with complex I inhibitor after the onset of AD-like neuropathology improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human AMP-AD transcriptomic data demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients. Copy rights belong to original authors. Visit the link for more info

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

The death rate from cancer has steadily declined over the past 25 years; however, worldwide there were 9.6 million deaths in 2018, with lung cancer still number one among all cancer types. In the latest episode of “Beyond the Abstract,” a program that explores the “whys” behind an article in The Annals of Thoracic Surgery, Dr. Kemp H. Kernstine joins host Dr. Tom Varghese to discuss whether tumor FDG-PET avidity represents enhanced glycolytic metabolism in non-small cell lung cancer. Read the related Annals article online: https://bit.ly/3c9sXm5.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.01.071662v1?rss=1 Authors: Jamadar, S. D., Ward, P. G. D., Liang, E. X., Orchard, W. R., Chen, Z., Egan, G. Abstract: Simultaneous FDG-PET/fMRI ([18F] fluorodeoxyglucose positron emission tomography functional magnetic resonance imaging) provides the capacity to image two sources of energetic dynamics in the brain, glucose metabolism and haemodynamic response. Functional fMRI connectivity has been enormously useful for characterising interactions between distributed brain networks in humans. Metabolic connectivity based on static FDG-PET has been proposed as a biomarker for neurological disease; but static FDG-PET cannot be used to estimate subject-level measures of connectivity, only across-subject covariance. Here, we applied high-temporal resolution constant infusion functional PET (fPET) to measure subject-level metabolic connectivity simultaneously with fMRI connectivity. fPET metabolic connectivity was characterised by fronto-parietal connectivity within and between hemispheres. fPET metabolic connectivity showed moderate similarity with fMRI primarily in superior cortex and frontoparietal regions. fPET metabolic connectivity showed little similarity with static FDG-PET metabolic covariance, indicating that metabolic connectivity is a non-ergodic process that cannot be used to infer individual-level connectivity from across-subject covariance. In sum, our results highlight the complementary strengths of fPET and fMRI in measuring the intrinsic connectivity of the brain, and opens up the opportunity for new multivariate metabolic neuroimaging biomarkers for neurological disease Copy rights belong to original authors. Visit the link for more info

Covered in this course is a review of the clinical and pathophysiological criteria in diagnosing Alzheimer’s dementia. The concept of mild cognitive impairment (MCI) and its relation to Alzheimer’s disease will be presented. The role of FDG PET as well as a discussion of new beta amyloid tracers in the evaluation of MCI and Alzheimer’s […]

Um caso de Febre de Origem Indeterminada (FOI)! O Frederico trouxe esse caso desafiador pra gente discutir e estruturar uma abordagem. A FOI é uma síndrome clássica da clínica médica, um mistério repleto de pistas falsas e verdadeiras. Vem com a gente tentar descobrir a causa dessa febre! REFERÊNCIAS: PETERSDORF, ROBERT G., and PAUL B. BEESON. "Fever of unexplained origin: report on 100 cases." Medicine 40.1 (1961): 1-30. DURACK, D. T. Fever of unknown origin-reexamined and redefined. Current Clinical Topics in Infectious Disease, v. 11, p. 35-51, 1991. BLEEKER-ROVERS, Chantal P. et al. Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation. European journal of nuclear medicine and molecular imaging, v. 31, n. 1, p. 29-37, 2004. DE KLEIJN, Elisabeth MHA; VAN DEN BROUCKE, Jan P.; VAN DER MEER, Jos WM. Fever of unknown origin (FUO): I. A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. 1997. HOROWITZ, Harold W. Fever of unknown origin or fever of too many origins?. The New England journal of medicine, v. 368, n. 3, p. 197, 2013. BLEEKER-ROVERS, Chantal P. et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine, v. 86, n. 1, p. 26-38, 2007. PETERSDORF, Robert G. Fever of unknown origin: an old friend revisited. Archives of internal medicine, v. 152, n. 1, p. 21-22, 1992. DRENTH, Joost PH et al. Metastatic breast cancer presenting as fever, rash, and arthritis. Cancer, v. 75, n. 7, p. 1608-1611, 1995. BOR, David H. Approach to the adult with fever of unknown origin. UPTODATE Jan 2020. BOR, David H. Etiologies of fever of Unknown origin in adults. UPTODATE Jan 2020. DHALIWAL, Gurpreet; DETSKY, Allan S. The evolution of the master diagnostician. JAMA, v. 310, n. 6, p. 579-580, 2013. HOT, Arnaud et al. Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Archives of internal medicine, v. 169, n. 21, p. 2018-2023, 2009. Knockaert, Daniel C., Laurent J. Vanneste, and Herman J. Bobbaers. "Fever of unknown origin in elderly patients." Journal of the American Geriatrics Society 41.11 (1993): 1187-1192.

Insomnia is a uniquely vexing medical problem. It is the most common sleep-related issue, thought to affect around 10-40% of the population in the US. So it is a challenge that affects a whole lot of us. Yet despite its prevalence, treatments for the condition are lackluster at best. Why is this the case? Perhaps because it remains poorly understood. Insomnia has been known and documented for thousands of years, but it has proven to be difficult to study for a number of reasons. It's hard to develop good animal models for the condition, it's difficult to objectively define, and symptoms manifest quite differently in individuals. In order to address a complex disorder like insomnia, we need to get to the root cause. Generally speaking, it seems clear that the origin lies within the brain. This has compelled some very clever researchers to take snapshots inside the heads of patients with insomnia (via positron emission tomography, or PET), and compare them to normal controls. The results of such studies have been enlightening. And that brings me to our guest for this episode. In this episode of humanOS Radio, Dan speaks with Eric Nofzinger. Dr. Nofzinger has spent more than 35 years practicing sleep medicine and studying the neurobiology of insomnia at the University of Pittsburgh School of Medicine. As a researcher at Pittsburgh, Dr. Nofzinger frequently interacted with patients with insomnia. They would often attribute their inability to sleep to a “racing mind.” If you've ever had trouble falling asleep due to incessant rumination, that characterization probably sounds pretty relatable. Furthermore, they would often claim to have hardly slept at all, even when polysomnography showed that they had experienced normal sleep. He, along with other scientists in the field, suspected that there was a biological basis for these commonly reported complaints. To gain meaningful insight into what was going on, he couldn't just look at sleep patterns - he needed to look inside the brain. To that end, he started conducting functional imaging studies on patients with insomnia to examine patterns of brain activity and metabolism during sleep. In one such trial, subjects completed regional cerebral glucose metabolic assessments while awake and while asleep using the FDG PET method. These scans were telling. During normal healthy sleep, there are typically substantial reductions in brain activity, particularly in the frontal cortex. But imaging for individuals with insomnia painted a very different picture. Their brains remained comparatively active during sleep, particularly in the frontal cortex, and they exhibited greater cerebral glucose metabolism during sleep and while awake. So, when these people claimed that their minds were racing throughout the night - when their brains should have been resting - that was actually a remarkably accurate assessment. These kinds of studies demonstrate that insomnia is, in essence, a disorder of hyperarousal of the brain. With this revelation, what can be done to slow down the racing mind? Cooling it down. It has been known for some time that application of a cooling stimulus to the head can lower the brain temperature in the underlying cortex, and in turn reduce brain metabolism. This insight led to the development of Ebb, a sleep therapy unlike any other that has yet been invented. Here's how it works: the device is comprised of a headband attached to a bedside unit. Cold fluid circulates through the forehead pad from the bedside unit, keeping your forehead at a cool temperature throughout the night. In this way, Nofzinger and his colleagues hope to target the root cause of insomnia, calming the mind and body. To learn more about Ebb and Dr. Nofzinger's research, check out the interview!

This JCO Podcast provides observations and commentary on the JCO article, "Treatment of Childhood Nasopharyngeal Carcinoma with Induction Chemotherapy and Concomitant Chemoradiotherapy: Results of the Children’s Oncology Group ARAR0331 Study" by Rodriguez-Galindo et al. My name is Suzanne Wolden, and I am the Director of Pediatric Radiation Oncology at Memorial Sloan Kettering in New York City, USA.  My oncologic specialty is Pediatric Radiation Oncology. This important manuscript summarizes the results of Children’s Oncology Group protocol ARAR0331 for childhood nasopharyngeal carcinoma.  The study enrolled 111 patients, of whom 75% were male and 47% were African American, with a median age of 15.  Eligible patients had AJCC stage IIb-IVC disease and received three cycles of induction chemotherapy with 5-fluorouracil and cisplatin followed by concurrent cisplatin and radiotherapy.  Three patients had progressive disease during induction chemotherapy, eight were removed from the study due to physician or parent preference, and another three were not evaluable.  This left 97 patients evaluable for response and concurrent chemoradiotherapy.  Responses and radiotherapy treatment plans were not centrally reviewed but were left to the judgement of the treating institution.  All patients received 45 Gy to comprehensive head and neck fields encompassing the nasopharynx and bilateral level I-V lymph nodes.  A boost to the nasopharynx and residual gross nodal disease was prescribed based on response.  The full dose of 70.2 Gy indicated for stable disease was given to 18.6% of patients while 77.3% received the protocol specified dose for complete or partial response of 61.2 Gy or lower.  Another 4.1% of patients received intermediate non-protocol doses of 63.9-66.6 Gy.  The trial was amended to reduce the cycles of concurrent cisplatin during radiotherapy to two from three after unacceptable rates of renal and gastrointestinal toxicities were reported.    This trial was limited to patients age 18 years and younger and consisted primarily of American patients.  It is notable that the demographics of nasopharynx cancer in these young patients differ significantly from adults with this diagnosis.  Most patients are teens since nasopharynx cancer is vanishingly rare in younger children.  The majority were male, and nearly half were African-American.  Nasopharynx cancer is quite rare in teens of Asian descent, in stark contrast to the adult population.  In international series, it has been noted that teens in countries around the Mediterranean also have a relatively high incidence of this rare cancer.  The study illustrates that pediatric patients are much more likely than adults to have advanced disease and WHO type III, Epstein Barr virus-associated histology. Despite a lack of central review, the response rate appears to be quite high to induction therapy as one might expect with WHO type III carcinoma.  It is surprising that any patients had progressive disease, and I suspect that the rate of partial and complete response may have been even higher than what is inferred from the radiation boost doses given.  Nonetheless, the strategy of induction therapy was highly successful in allowing a large majority of patients to receive reduced doses of radiation.  It is important to note that all patients received 45 Gy to initial comprehensive fields rather than the 50 Gy typically used for adults and that smaller, more forgiving fractions of 1.8 Gy were used in comparison to the standard 2 Gy for adult head and neck cancer.  While some patients received a standard adult boost dose of 70.2 Gy, 81.4% received a lower boost dose.  In most cases, this was the protocol specified 61.2 Gy, a 13% dose reduction.  Even with these significantly lower doses, local control was exceptionally high, with only 5.5% of patients experiencing local failure with or without a distant relapse. The successful reduction in radiotherapy doses in this study is incredibly important and by far the most newsworthy aspect of this paper.  Even full or nearly grown teens experience dramatically more severe late effects of radiotherapy compared to older adults.  The severity of soft tissue fibrosis 10 or more years after full doses of radiation to the head and neck is so great that many patients require feeding tubes and tracheostomies.  The rate of second malignancy is also much higher in young patients.  The rate of distant relapse of 10.5% was low, considering that patients with metastatic disease at diagnosis were enrolled.  It is possible that with more advanced staging scans such as FDG-PET, metastatic lesions can be more easily detected and defined.  In that case, they can be targeted with radiotherapy to decrease the risk of relapse.  This approach has been shown to be effective in achieving cure in adults.  It is unlikely that an increase in chemotherapy beyond what was used in this protocol would be tolerated or worth the added toxicity.  Indeed, it is unclear whether the 3rd cycle of concurrent cisplatin was beneficial since there was only a trend for improved EFS and the cumulative toxicity is significant.  One must be mindful that increases in systemic therapy have been shown to decrease tolerance for head and neck radiotherapy.  This can be counterproductive to outcome if there are delays, breaks or failure to complete the course of radiation. This trial was so successful in its ability to decrease radiation exposure in young patients, that we should be inspired to go further.  My thoughts regarding the next trial would be to use PET scans for staging and response assessment and to push the radiotherapy doses lower.  This approach is currently being investigated for adult HPV associated head and neck cancer with doses as low as 30 Gy.  Perhaps in pediatric (or even EBV positive adult) nasopharynx cancer, 30-36 Gy would be enough for the comprehensive initial fields with boost doses in the range of 50-60 Gy for those who respond favorably to induction chemotherapy.  Dose reductions of this magnitude would make major differences in the acute and especially the late toxicities.  In addition, modern radiation technologies such as proton therapy allow improved avoidance of normal tissue exposure for these young, curable patients. In summary, this article provides evidence that response-based radiation dose reduction is possible for pediatric nasopharynx cancer.  Even with numerous limitations, the outstanding results of this trial inspire us to continue moving forward in the direction of reducing radiation exposure for these young patients.  Long-term follow up is also urged to quantify the expected benefits of these therapeutic changes. This concludes this JCO Podcast.  Thank you for listening.

“Value of 12-lead electrocardiogram to predict myocardial scar on FDG PET in heart failure patients”. In this episode, Susanne Markendorf summarizes the above study, highlights the new information, clinical implications and limitations of the study, and provides suggestions for future studies. 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: https://link.springer.com/article/10.1007/s12350-019-01841-6#SupplementaryMaterial The article is available at: https://rdcu.be/bOyfD Be sure to subscribe on your mobile device - search 'JNC/ASNC Podcast'.

In this episode of the JNC/ASNC Podcast, Fadi Hage and Mehran Sadeghi discuss the paper entitled ‘FDG PET imaging of vascular inflammation in post-traumatic stress disorder: A pilot case–control study’. 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/2Y6PcqW The article is available at: http://bit.ly/2Yj07J1 Be sure to subscribe on your mobile device - search 'JNC/ASNC Podcast'.

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.

On 1st March 2019, Valeria Gaudieri spoke with Heikki Tuominen about the recently published article entitled ‘FDG-PET in possible cardiac sarcoidosis: Right ventricular uptake and high total cardiac metabolic activity predict cardiovascular events.’ 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/2ITAESo The article is available at: http://bit.ly/2uaTJqK Be sure to subscribe on your mobile device - search 'JNC/ASNC Podcast'.

This week I'll tackle an interesting topic in giant cell vasculitis - the utility of FDG PET. This was a good paper but one that I used to discuss important concepts, including negative predictive value and pretest probability.  Hope you enjoy!  Please give feedback @EBRheum! Find all the papers here: https://tinyurl.com/yyll5qof

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.  

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 from this month’s issue. We’ll also hear from Dr. Suraj Kapa reporting on new research for the latest journal articles in the field.                                                 The first article in this month's issue is by Yoav Michowitz and Associates who examine the morphological ECG characteristics of left posterior fascicular ventricular tachycardia and differentiated from right bundle branch block and left anterior hemiblock aberrancy. 183 ECGs with left posterior fascicular ventricular tachycardia in patients who underwent ablation were identified using a systematic Medline search were examined and compared to 61 ECGs with right bundle branch block in left anterior hemiblock aberrancy with no obvious cardiac pathology by echocardiography.                                                 Using four variables including atypical right bundle branch block like V1 morphology, positive QRS in aVR, V6R greater than S ratio of less than one and QRS less than or equal to 140 ms, a prediction model was developed that predicted posterior fascicular ventricular tachycardia with a sensitivity of 82% and a specificity of 78%. Patients with three out of four positive variables had a high probability of having left posterior fascicular ventricular tachycardia whereas patients with less than or equal to one positive variable always had right bundle branch block plus left anterior hemiblock.                                                 In the next article, Anna Thøgersen and associates describe a case series of 10 patients in whom implantable cardioverter defibrillators failed to treat ventricular tachyarrhythmias. The authors examine whether consensus derive generic rate threshold cutoffs between 185 and 200 beats per minute were employed in this case series. In nine patients, ventricular fibrillation did not satisfy program detection criteria. Five patients died with untreated ventricular fibrillation, four had cardiac arrest requiring external shocks and one was rescued by a delayed ICD shock. Seven of these patients had slowest detection rates that were consistent with generic recommendations but not tested in a peer review trial for their manufacturer’s ICDs.                                                 In the reported cases, manufacturer specific factors interacted with fast detection rates to withhold therapy including strict ventricular fibrillation episode termination rules, enhancements to minimize T-wave over sensing and features that restrict therapy to regularly rhythms in VT zones. Untreated ventricular fibrillation despite recommended programming accounted for 56% of the deaths and 11% of all of deaths. The authors concluded that complex and unanticipated interactions between manufacturer specific features and generic programming can prevent therapy for ventricular fibrillation.                                                 In the next article, Miguel Rodrigo and associates describe from 17 simulations of atrial fibrillation, atrial flutter and focal atrial tachycardia the ability to understand signal processing that can affect identification of reentrant activity using electrograms, body surface potential mapping and electrocardiographic imaging ECGI phase maps. Reentrant activity was identified by singularity point recognition and raw signals and in signals after narrow band pass filtering at the highest dominant frequency.                                                 Reentrant activity was identified without filtering in 60% of unipolar records but filtering was required to increase reentrant activity detection from 1% to 62% in bipolar recordings. The filtering resulted in residual false reentrant activity in about 30% of bipolar recordings. The authors concluded that rotor identification is accurate and sensitive and does not require additional signal processing in measured or noninvasively computed unipolar electrograms while bipolar electrograms and body surface potential mapping do require highest dominant frequency filtering in order to detect rotors at the expense of a decrease specificity.                                                 In the next article, Raymond Yee and associates examine the ability of a new automated antitachycardia pacing algorithm to reduce ICD shocks. The new automated ATP algorithm was based on electrophysiologic first principles and prescribed the ATP sequences in real time using the same settings for all patients. In 144 patients who had dual chamber or CRT ICDs as well as a history of one or more ICD treated VT or VF episodes or a recorded sustained monomorphic ventricular tachycardia episode. Detection was sent to ventricular fibrillation interval detection of 24 out of 32 ventricular tachycardia interval detection of 16 or greater in a fast VT zone of 242 to 320 ms.                                                 There were 1,626 treated episodes in 49 patients over 14.5 month’s follow up. Data logs permitted adjudication of 702 episodes including 669 sustained monomorphic ventricular tachycardia episodes, 20 polymorphic ventricular tachycardia episodes, 10 SVT episodes and three mal sensing episodes. The novel automated antitachycardia pacing algorithm terminated 39 out of 69 episodes or adjusted 59% of the sustained monomorphic ventricular tachycardia events in the fast VT zone, but 509 out of 590 or 85% adjusted in the VT zone and 6 out of 10 in the VF zone. No SVTs were converted to VT or VF and no anomalous ATP behavior was observed. The authors concluded that this new automated ATP algorithm could be used safely in all zones without need for individualized programming.                                                 In the next study Pablo Ávila and associates studied the incidence and clinical predictors of atrial tachycardias in adults in a cohort of 3,311 patients with congenital heart disease. Prospectively followed in a tertiary center for 37,607 person years. The study patients were divided into three categories; 49% simple, 39% moderate and 12% complex congenital heart disease. In this cohort, 153 or 4.6% of patients presented with atrial tachycardia. The atrial tachycardia burden was highest in complex congenital heart disease such as single ventricle 22.8% or D-TGA 22.1%.                                                 The authors found that univentricular physiology, previous intracardiac repair, systemic right ventricle, pulmonary hypertension, pulmonary regurgitation, pulmonary AV valve regurgitation and pulmonary and systemic ventricular dysfunction were independent risk factors for developing atrial tachycardia. At the age of 40 years, atrial tachycardia free survival in patients with zero risk factors was 100%. With one risk factor, it was 94%. With two risk factors was 76% and three or more risk factors was 50%. These authors confirm these findings in a validation cohort.                                                 In the next article, Khidir Dalouk and associates compare clinical outcomes between ICD patients followed up in a telemedicine videoconferencing clinic and a conventional in person clinic. In this retrospective study, the authors compared time to first appropriate ICD therapy, time to first inappropriate ICD therapy, time to first shock and overall survival. The authors studied 287 patients in the telemedicine videoconferencing clinic group and 236 patients in the conventional in person clinic over mean follow-up duration of 4.8 years. The authors found that telemedicine videoconferencing clinic was not inferior to in person follow-up for the pre-specified outcomes.                                                 In the next article, Elisabeth Mouws and associates studied the epicardial breakthrough waves in sinus rhythm possibly giving insight to the arrhythmogenic substrate in atrial fibrillation. In 381 patients with ischemic or valvular heart disease, intraoperative epicardial mapping with intro electro distance of 2 mm was performed of the right atrium, Bachmann’s bundle, the left atrioventricular groove and the pulmonary vein area. Epicardial breakthrough waves were referred to as sinus node breakthrough waves if they were the earliest right atrial activated site. A total of 218 epicardial breakthrough waves and 57 sinus node breakthrough waves were observed in 168 patients or 44%.                                                 Epicardial breakthrough waves mostly occurred at the right atrium and 48% at the left atrioventricular groove and 31% followed by Bachmann’s bundle and 12% and the pulmonary vein area and 9%. Epicardial breakthrough waves occurred most often in ischemic heart disease patients 49% to valvular patient's 17%. Epicardial breakthrough wave electrograms most often consisted of double or fractionated electrograms seen in 63%. Fractionated epicardial breakthrough wave potentials were more often observed at the right atrium or Bachmann's bundle. The authors concluded that epicardial breakthrough waves are present in over a third of patients possibly indicating muscular connections between the endocardium and epicardium that may enhance the occurrence of epicardial breakthrough waves during atrial fibrillation promoting AF persistence.                                                 In the next article, Shouvik Haldar and associates compare horizontal and vertical orientation bipolar electrograms with novel omnipolar peak to peak voltages in sinus rhythm and atrial fibrillation using a high density fixed multi-electrode plaque placed on the epicardial surface of the left atrium in dogs. Bipolar orientation had significant impact on bipolar electrogram voltages obtained either in sinus rhythm or atrial fibrillation. Omnipole Vmax values were 99.9% larger than both horizontal or vertical electrograms in sinus rhythm in larger than horizontal or vertical electrograms in atrial fibrillation.                                                 Further vector analysis of omnipole electrograms showed that omnipolar electrograms can record electronic voltage unaffected by collision and fractionation. The authors concluded that omnipolar electrograms can attract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation compared to contemporary bipolar techniques.                                                 In our final article for the month, Pauline Quenin and associates examine the efficacy of screening in relatives of subjects who died suddenly. The authors provided clinical screening to 64 families who experienced unexplained sudden cardiac death before age 45 in a prospective multicenter registry. The diagnosis was established in 16 families, 25% including Brugada syndrome, long QT syndromes, dilated cardiomyopathy and hypertrophic cardiomyopathy. The diagnostic yield was mainly dependent on a number of screen relatives with 3.8 screen relatives in the diagnosed family versus 2.0 in the non-diagnosed families rising to 40% with at least three relatives.                                                 It additionally increased from 9% to 41% when both parents were screened. Diagnostic performance was also dependent on the exhaustiveness of the screening. 70% of complete screening versus 25% with incomplete screening with 17 Brugada syndrome and 15 long QT syndrome diagnoses based on pharmacologic tests. The authors concluded that even without autopsy, familial screening after sudden death in young patients is effective greatly increasing the likelihood of diagnosis in families.                                                 That's it for this month but keep listening. Suraj Kapa will be surveying all journals for the latest articles on topics of interest in our field. Remember to download the podcast On the Beat. Take it away Suraj. Suraj Kapa:                          Thank you Paul. It is my pleasure to welcome everybody back to our continued series of On the Beat articles from across the electrophysiology literature especially selected to highlight their potential importance in terms of either current or future practice within the realm of cardiac electrophysiology. Again, my name is Suraj Kapa and it is my pleasure to walk us through a variety of hard-hitting articles.                                                 Today we’ll be starting within the realm of atrial fibrillation specifically as it relates to cardiac mapping and ablation. The first article was by Iwasawa et al entitled Temperature Controlled Radiofrequency Ablation for Pulmonary Vein Isolation in Patients with Atrial Fibrillation published in volume 70 of the Journal of the American College of Cardiology. In this article, Iwasawa and colleagues discuss the role of novel temperature controlled irrigated ablation catheter to attempt to obtain deeper transmural lesions in cardiac tissue, specifically they tested the utility of a diamond embedded tip for rapid cooling accompanying six surface thermocouples to better reflect tissue temperature.                                                 They demonstrated in this first in human series that a temperature controlled irrigated ablation could produce rapid, efficient and durable PV isolation. The importance of this particular article lies in the continued development of novel tools that can achieve pulmonary vein isolation either more safely or more quickly. This was highlighted in the article by Iwasawa et al when they demonstrated that the mean radiofrequency application duration was significantly less by almost a factor of three and those using the novel radiofrequency ablation catheter versus those with older models.                                                 They also noted that there was lower acute dormant pulmonary vein re-conduction rates and patients tend to have more frequent durable isolation when remapped after ablation. While the study group only consisted of 35 patients within the treatment group and 35 patients within the control group, the potential of these novel catheters to achieve aims of both shortening procedure duration as well as improving procedure and success need to be taken in consideration.                                                 The next article is by Dr. Gopinathannair entitled Atrial Tachycardia after Surgical Atrial Fibrillation Ablation Clinical Characteristics, Electrophysiological Mechanisms and Ablation Outcomes from a large multicenter study published in the August 2017 issue of JACC Clinical Electrophysiology. In this article, Dr. Gopinathannair reviews the outcomes of cardiac mapping and ablation targeted atrial tachycardias occurring after surgical atrial fibrillation ablation. They reviewed a large number of patients nearly 137 undergoing catheter ablation for symptomatic postsurgical atrial fibrillation ablation atrial tachyarrhythmias across three high volume institutions in the United States.                                                 They demonstrated that the vast majority had a left atrial origin though up to a third also had a right atrial origin further atrial tachyarrhythmias. The predominant circuits noted were cavotricuspid isthmus but also frequently perimitral roof and left or right pulmonary veins. In addition, most of the patients namely 93% had at least one pulmonary vein reconnection requiring re-isolation. The key point with the article however were the outcomes. They demonstrated that acute termination inducibility could be achieved in as many as 97% of right atrial and 93% of left atrial tachyarrhythmias in the setting of prior surgical ablation.                                                 Furthermore, 12 month followup demonstrated an 80% success rate. Traditionally, surgical atrial fibrillation ablation is seen as a complex procedure with the remapping of arrhythmias requiring a lot more complexity. However, these findings cross a large group of patients suggesting that we can have a high rate of success should propose to individuals that perhaps targeted ablation at these postsurgical atrial tachyarrhythmias should be amenable towards ablation especially at high volume complex ablation centers.                                                 Next will discuss the article by Pathik et al entitled Epicardial-Endocardial Breakthroughs through Stable Macroreentry: Evidence from ultra-high-resolution three-dimensional mapping published in Heart Rhythm in August 2017. In this article, the group of Pathik et al decided to review whether epicardial-endocardial breakthrough could be discerned during stable right atrial macroreentry using high density and high spatial resolution three-dimensional mapping. Twenty-six patients were studied and they noted that up to 14 patients had evidence of epicardial-endocardial breakthrough. Using systematic entrainment confirmation, stable atrial macroreentry with epicardial-endocardial breakthrough was consistently demonstrated.                                                 The principle of epicardial-endocardial breakthrough or dissociation is critically important during cardiac mapping. While widely accepted for ventricular mapping, the tradition because of lack of available tools and atrial mapping has suggested that endocardial only mapping should reveal the entire cardiac circuits. Advances in signal processing as well as cardiac mapping techniques and technologies has allowed for better discernment of potentially deeper manifestations of cardiac tissue involvement in cardiac arrhythmias. As been well recognized that there can be significant epicardial and endocardial dissociation in cases of persistent atrial fibrillation.                                                 The article by Pathik et al is important in that it highlights that such events can manifest themselves even in the setting of relatively organized or stable atrial macroreentry. Part of the reason this becomes so critical is that when we consider endocardial only remapping and rely on these signals alone, we may run into situations where we miss a significant chamber of atrial tissue namely the epicardium, thus the focus of this article and the consideration of it in the clinician's repertoire of cardiac mapping and ablation should lie in an understanding of the fact that the entire story of an electrical circuits may not be told by traditional endocardial mapping alone without consideration for epicardial-endocardial breakthrough.                                                 The next article we will focus on is by Dr. Chun et al regarding the impact of cryoballoon versus radiofrequency ablation for paroxysmal atrial fibrillation on healthcare utilization and costs and economic analysis. This was from the FIRE and ICE Trial published in the Journal of the American Heart Association this past month. In this study they sought to assess payer cost following cryoballoon or radiofrequency catheter ablation for paroxysmal atrial fibrillation. They demonstrated that there are cost savings of as much as $355,000 related to the use of cryoballoon over traditional radiofrequency catheter ablation. This reduction in resource use and payer costs was consistent across three different national healthcare systems.                                                 Furthermore, the reason for the reduced cost was primarily attributable to fewer repeat ablations and a reduction in cardiovascular rehospitalizations with cryoballoon ablation. In this era of cost reduction, it is important to consider the potential implications of use of novel technologies in terms of procedural costs. The ability to identify novel techniques that can actually both reduce costs and either achieve equal or improved outcomes needs to be strongly considered. While the three national healthcare systems reviewed here might not reflect all healthcare systems or all insurance needs, it still brings up an important economic consideration that all novel technology may not necessarily result in increased costs, and utilization must be considered both in the context of the particular system as well as the particular provider.                                                 Changing pace, we’ll move on with an atrial fibrillation to the role of anticoagulation. The first major article recently published is by Pollack et al regarding the use of Idarucizumab for dabigatran Reversal, the full cohort analysis published the New England Journal of Medicine. Idarucizumab is a monoclonal antibody fragments developed to reverse the anticoagulant effect with dabigatran and represents the first reversal agent available for reversal of any of the novel oral anticoagulant drugs. In this study which is both multicenter, prospective and open label, patients were enrolled to undergo treatment with this reversal agents.                                                 A total 503 patients were included and the median maximum percentage reversal dabigatran was 100% which was measured using the diluted thrombin time or the ecarin clotting time. In those with active bleeding, the median time to cessation of bleeding was around 2.5 hours. Furthermore, in a surgical cohorts who underwent reversal in order to accommodate them going to surgery, the time to initiation of an intended procedures was 1.6 hours with periprocedural hemostasis assessed as normal in 93%, mildly abnormal in 5% and moderately abnormal in 1.5%. Thrombotic events occurred in about 6.3% of patients undergoing reversal because of active bleeding and then 7.4% undergoing reversal for surgical accommodation.                                                 Mortality rates were around 18% to 19%. Thus it was demonstrated that in emergency situations Idarucizumab can rapidly, durably and safely reverse the anticoagulant effect of dabigatran. However, it is important to note that there was a signal for thrombotic events and consideration of the risk of rapid reversal of anticoagulation regardless of the type of anticoagulation in combination with the actual need for reversal should be considered in the patient context.                                                 The next article we will review is by Jackevicius et al entitled Early Non-persistence with Dabigatran and Rivaroxaban in Patients with Atrial Fibrillation, published in Heart this past month. In this article, the group reviewed how patients manage being on their novel oral anticoagulants over the course of time after initial diagnosis and prescription. One of the concerns regarding novel oral anticoagulants is given the fact that there is no actual tracking or no actual measurements needed to ensure continued adherence to the drug, whether or not there will be higher rates of nonpersistence with use of these novel oral anticoagulants.                                                 Amongst 15,857 dabigatran users and 10,119 rivaroxaban users, they noted that at six months about a third of patients were nonpersistent with either drug. In those patients who were nonpersistent with use of the drug, the combined endpoint of stroke, TIA and death was significantly higher with hazard ratios of 1.76 in the dabigatran cohort and 1.89 in the rivaroxaban cohort. Furthermore, the risk of stroke or TIA was markedly higher in nonpersistent patients with about a hazard ratio of 3.75 in dabigatran nonpersistence and 6.25 in rivaroxaban nonpersistence.                                                 Given these relatively high rates of nonpersistence in clinical practice and the negative outcomes associated with nonpersistence, this highlights the importance of continued validation of the need for persistence with use of oral anticoagulation in patients prescribed these perceived to be at high risk of stroke associate with atrial fibrillation. In an era of improving drug use or improving drugs that can be used without the need for blood testing, it must also be considered that these drugs may be more easily stopped on the patient's own discretion without any knowledge from a provider as there is no active blood test associated. Thus this further highlights the importance of continued discussion between patients and physicians over the course of therapy and care regarding the need for continuation.                                                 Changing paces. We review the article by Godier et al entitled Predictors of Pre-procedural Concentrations of Direct Oral Anticoagulants a prospective multicenter study published at the European Heart Journal. We all know that one of the major issue with a direct oral anticoagulants is that these patients frequently undergo elective invasive procedures and in this setting the management can be very challenging specifically as it relates to when the direct oral anticoagulants should and can be safely stopped.                                                 In clinical practice, there is wide variability in the timing by which providers inform patients to stop these new oral anticoagulants prior to invasive procedure. In this prospective multicenter study, 422 patients were evaluated with preprocedural DOAC concentrations and routine hemostasis assays performed to determine those patients who achieved a minimal preprocedural concentration based on the timing of their discontinuation of the drug. They ranged the duration of discontinuation of the oral anticoagulant from 1 to 218 hours. They noted after a 49 to 72 hour discontinuation period, 95% of the concentration of the direct oral anticoagulants in patients had levels that were significantly low suggesting safety and proceeding with any sort of invasive procedure.                                                 Thus a 72 hour discontinuation period predicted sufficiently low concentrations of DOACs with 91% specificity. In multivariable analyses, duration of the DOAC discontinuation with creatinine clearances and antiarrhythmics were independent predictors of a minimal preprocedural DOAC concentration, namely better renal function, longer duration of DOAC discontinuation and interestingly the use of antiarrhythmic drugs were all associated with lower DOAC concentrations. The conclusion from this article was a last DOAC intake of three days before a procedure resulted in a minimal preprocedural anticoagulant effect for almost all patients considered.                                                 The exception would be in moderate renal impairment especially in dabigatran treated patients and antiarrhythmics in anti-Xa-treated patients could result in the need for longer DOAC interruption. Thus, the key things here to note are that antiarrhythmics can result in the need for longer DOAC interruption to achieve minimal blood concentrations and that similarly moderate renal impairment especially in dabigatran treated patients may result in the same. Another outcome other studies suggested a lack of association between routine assays such as routine hemostasis assays and DOAC concentrations suggesting that in situations where testing is believed to be needed routine assays should not replace DOAC concentration measurement in decision-making regarding whether or not the DOAC has sufficiently gone down in concentration to safely proceed.                                                 Along these lines, the final article we will review within the realm of anticoagulation is by Brendel et al entitled the Anticoagulant Effect of Heparin during Radiofrequency Ablation in Patients Taking Apixaban or Rivaroxaban published in the Journal of Interventional Cardiac Electrophysiology this past month. One concern regarding the use of the direct oral anticoagulants is the fact that during procedures where heparin is needed, knowledge of how much heparin to give is unclear. This is both in the setting of understanding what the synergistic effect of the simultaneous and continued use of apixaban or rivaroxaban or other direct oral anticoagulants in combination with heparin might be and also what the effect on actual activated coagulation time might be.                                                 As it is felt that be ACT may not necessarily reflect the true anticoagulant activity of drugs. Thus in a prospective study, Brendel et al studied about 90 patients with atrial fibrillation undergoing radiofrequency ablation procedures. During radiofrequency ablation, unfractionated heparin was given to maintain ACT of 250 to 300 ms with blood samples taken before and up 360 minutes after heparin administration. They demonstrated that heparin displayed a lower anti-Xa activity in rivaroxaban treated patients compared to apixaban treated patients.                                                 In contrast, D-dimer and prothrombin fragment F1+2 plasma levels indicated a higher activation of the coagulation cascade in apixaban/heparin combinations than in rivaroxaban/heparin combinations. While there was clear differences in the level of anticoagulant effect, depending on which DOAC was combined with heparin, they had no clinical impact in terms of bleeding or thromboembolic complications from the procedure. This article is significant in that it highlights that there are clear and different biochemical responses based on which DOAC is used in combination with heparin during radiofrequency ablation.                                                 While in the small study, there was no clear effect on clinical impact, precautions should still be considered when monitoring periprocedural hemostasis in DOAC patients to avoid mismanagement especially considering the variability that might occur between DOACs themselves and not just between DOACs and warfarin.                                                 Changing paces to risk stratification and management within atrial fibrillation. We’ll review the article by Labombarda et al entitled Increasing Prevalence of Atrial Fibrillation and Permanent Atrial Arrhythmias in Congenital Heart Disease published in this past month's issue of the Journal the American College of Cardiology. In this article, they sought to assess the types and patterns of atrial arrhythmias, associate factors and age-related trends in a multicenter cohort of patients with adult congenital heart disease. What they demonstrated is that by far the most common presenting arrhythmia was intraatrial reentrant tachycardia in almost two-thirds of patients with the remaining including atrial fibrillation in up to 30% of patients and focal atrial tachycardias in up to 10% of patients.                                                 The association of intraatrial reentrant tachycardia with congenital heart disease was stronger with higher complexities of congenital heart disease. With those with more complex defects having a higher frequency of IART than those with simple effects. Furthermore, as is commonly seen in the general population, the frequency of atrial fibrillation increased with age to eventually suppress IART as the most common arrhythmia in those greater than equal to 50 years of age. The predominant arrhythmia pattern was paroxysmal in almost two-thirds of patients though almost 30% were persistent.                                                 Furthermore, the frequency of permanent atrial arrhythmias increased with age. While it is commonly seen that patients with congenital heart disease were living longer and as a result it is expected that the frequency of arrhythmias in this population will likely increase. The interesting outcome from the study is the high frequency of intraatrial reentrant tachycardia as the presenting atrial arrhythmia in patients with congenital heart disease and also with the predominantly paroxysmal pattern. The finding also that atrial fibrillation increases in prevalence highlights the importance of closely monitoring these patients in order to assess for anticoagulation needs and options for treatment.                                                 Changing gears to cellular electrophysiology. We focus on an article by Qiao et al entitled transient Notch activation induces long-term gene expression changes leading to sick sinus syndrome in mice published in this past month's issue of Circulation Research. Notch signaling programs cardiac conduction during development and in the adult ventricle. It is noted that injury can induce notch reactivation resulting in global transcriptional and epigenetic changes. Thus, the group sought to determine whether notch reactivation may alter atrial ion channel gene expression arrhythmia inducibility.                                                 They demonstrated that notch signaling regulates transcription factor in ion channel gene expression in adult atrial myocardium. With reactivation inducing electrical changes resulting in sinus bradycardia, sinus pauses and a susceptibility atrial arrhythmias, altogether contributing to a phenotype resembling sick sinus syndrome. The importance of these findings lies in the mechanism underlying sick sinus syndrome.                                                 While we search for genetic clues for why patients might develop atrial fibrillation or sick sinus syndrome or sinus bradycardia as they age, the importance of activation of typically quiet signaling patterns in the adult myocardium and their role in arrhythmogenesis is important because it might highlight novel targets for treatment. Understanding how the arrhythmogenic substrate develops and the mechanisms underlying it, may allow for a better understanding of why in certain patients certain drugs may be effective or not or certain invasive therapies may be effective or not.                                                 Next with the realm of electrocardiography, we’ll review the article by Christophersen et al entitled 15 Genetic Loci Associated with Electrocardiographic P-wave published in Circulation Genetics this past month. Similar to the previous article by Dr. Qiao et al, the importance of the article by Christophersen et al lies in the identification of a number of genetic underpinnings for what forms the final electrocardiographic P-wave that is seen.                                                 Six novel genetic loci associated with P-wave duration and six novel loci associated with P-wave terminal force were identified by the group. Both in the case of the transient Notch activation findings as well as in the findings related to a specific genetic loci associated with electrocardiographic P-wave abnormalities might highlight potential genetic targets either with existing drugs not traditionally used for atrial electrophysiology or potentially future drug targets.                                                 Changing gears yet again, we’ll move on to their own sudden death cardiac arrest and specifically to an article published by Fallavollita et al entitled the denervated myocardium is preferentially associate with sudden cardiac arrest in ischemic cardiomyopathy a pilot competing risks analysis of cost specific mortality. Previous studies identify multiple factors associated with total cardiac mortality but we all recognize the ejection fraction has limited value. Thus within this article published in Circulation: Cardiovascular Imaging, the group decided to do a competing risks analysis the National Institutes of Health sponsored prediction of arrhythmic events with positron emission tomography trial.                                                 They demonstrated that sudden cardiac arrest was correlated with greater volumes of denervate myocardium based on defects on positron emission tomography using a norepinephrine analog carbon 11 hydroxy ephedrine. However, they also demonstrated that other factors such as lack of angiotensin inhibition therapy, elevated BNP and large left particular end-diastolic volume were further associated with sudden cardiac arrest.                                                 The importance of potential modifying factors to better attribute cardiac arrest risk and thus the need for defibrillator or other therapies in patients with myopathy needs to continue to be highlighted especially in light of recently published Danish and other studies suggesting that the mortality benefit conferred by ICD is an ischemic and nonischemic populations may not be equivalent in newer studies. The fact that further risk stratification opportunities can exist underlying the pathophysiologic basis for why these patients develop ventricular arrhythmias is critical. While recognized for a few decades now that myocardial denervation may be associated with sudden cardiac arrest risk, this study highlights the continued need for further study to help further clarify these populations.                                                 Moving onto the realm of genetic channelopathies, we review the article by Anderson et al entitled Lidocaine Attenuation Testing: An in vivo Investigation of Putative LQT3-Associated Variants in the SCN5A-encoded sodium channel published in this past month's issue of Heart Rhythm. Long QT syndrome type 3 represents one of the more difficult types of long QT syndrome to adequately diagnose both by genetic testing as well as through traditional means. Approximate 2% of healthy individuals can have rare variance of uncertain significance in the SCN5A channel and thus distinguishing true LQT3 causative mutations for background genetic noise can be quite difficult in this population.                                                 Anderson et al decided to assess the utility of lidocaine attenuation testing in evaluating patients with possible LQT3. They gave a loading dose of 1 mg per kg of intravenous lidocaine followed by continuous infusions of 50 micrograms for 20 minutes. If the corrected QT interval shortened by at least 30 ms, the LAT was defined as positive. They demonstrated that use of this test can help distinguish true LQT3 causative mutations from otherwise noncontributory variance of uncertain significance. Thus in this era of increasing genetic testing where one might identify a variant of uncertain significance in either a family member affected with sudden cardiac arrest or in a patient being evaluated for any sort of uncertain significant variant, the use of lidocaine testing in those variance as they apply to LQT type 3 may offer significant clinical use.                                                 Next we will review the article by Ishibashi et al published in this past month's edition of Heart entitled Arrhythmia Risk and Beta Blocker Therapy in Pregnant Woman with Long QT Syndrome. One of the biggest concerns of patients with long QT syndrome especially woman is pregnancy. The fact is because of the different hormonal states, it is possible that pregnancy may alter arrhythmic risk and the safety of beta blocker therapy given both the potential fetal effects as well as the continued efficacy at the level those seen previously.                                                 Thus Ishibashi et al reviewed 136 pregnancies across 76 long QT pregnant patients. They retrospectively analyzed clinical and electrophysiological characteristics in pregnancy outcomes in both the presence and absence of beta blocker therapy. All of the beta blocker group had prior events while the majority of the nonbeta blocker group had not been diagnosed with pregnancy. Pregnancy was noted to increase heart rate in those not treated with beta blockers, but interestingly, between the two groups there was no significant difference over the course of pregnancy in QT intervals.                                                 In the beta blocker group, only two events occurred and these were relegated to the postpartum period. However, 12 events occurred in the nonbeta blocker group either during pregnancy and half or in the postpartum period and the remaining half. There was no difference in this frequency of spontaneous abortion between the two groups, and furthermore, fetal growth rates and proportion of infants with congenital malformation were similar between the two groups. However, premature delivery and low birth weight infants were more common in those taking beta blockers.                                                 Given the high risk of events and the relative safety of beta blocker therapy in this population of patients with long QT who become pregnant, it was felt that the use of early diagnosis and beta blocker therapy could be critical both the during pregnancy and during the postpartum period. It was also felt the beta blocker therapy may be tolerated for babies in long QT pregnant patients. This highlights that the continued use of beta blockers throughout the pregnancy and consideration of the introduction of beta blockers in those not already on them during pregnancy may be an important consideration.                                                 Finally within the realm of genetic channelopathies, we focus on the article by Roberts et al entitled Loss of Function in KCNE2 Variants: True Monogenic Culprits of Long QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation published in this past month's issue of Circulation: Arrhythmia Electrophysiology. As we identify more and more genes the baby is associated with long QT syndrome, the understanding of the clinical phenotype associated with that syndrome requires better study. In this particular study, Roberts et al reviewed the role of long QT syndrome type 6 stemming from mutations in the KCNE2 encoded voltage gated channel beta subunits.                                                 They reviewed mutations identified during arrhythmia evaluation from either inherited arrhythmia clinics or the Rochester long QT syndrome registry. They demonstrated that the high allelic frequencies of LQT6 mutations in the Exome aggregation consortium database and the absence of previous documentation of genotype phenotype segregation suggest many KCNE2 variants and potentially all were actually erroneously designated as LQT as causative mutations. Instead, it was felt the KCNE2 variants may actually confer proarrhythmic susceptibility when provoked by additional environmental and/or acquired or genetic factors.                                                 What they are saying is that identifying the KCNE2 variants as the principal culprits may be over calling the role of the KCNE2 variants and instead it might be a combination of effects such as two hit affect the requires further provocation by either outside or additional genetic factors. Furthermore, complex genetic studies were likely needed to better understand how variants and genes that may not have been previously designated as disease causing play a role in the actual disease process, whether as potentiating other factors that might exist that might also otherwise be relatively benign or as unique singular hits that might by themselves result in the clinical phenotype.                                                 Next moving onto the realm of ventricular arrhythmias, we first focus on an article published in this past month's issue of the American Journal of Physiology, Heart and Circulatory Physiology by Howard Quijano et al entitled Spinal Cord Stimulation Reduces Ventricular Arrhythmias during Acute Ischemia by Attenuation of Regional Myocardial Excitability. In this article, they demonstrated in a porcine model ventricular ischemia that spinal cord stimulation decrease sympathetic nerve activation regionally in ischemic myocardium while having no effect on normal myocardium. They demonstrated that the antiarrhythmic effects conferred by spinal cord stimulation were likely secondary to attenuation of some sympathoexcitation locally in ischemic myocardium rather than changes in the global myocardial electrophysiology.                                                 This is important because it highlights the mechanisms by which spinal cord stimulation may confer in antiarrhythmic benefits in both animal and human models. As we search for novel interventions that can be used for the treatment of ventricular arrhythmias, understanding the underlying pathophysiologic mechanisms by which they work is critical. The understanding that the use of spinal cord stimulation is primarily conferred in a regional way primarily in terms of its effect on an ischemic myocardium, further study is also needed in terms of how the effect is seen in nonischemic myopathies where there may be more patchy scar in the same role of denervation, nerve sprouting and hyper innervation may play different roles.                                                 In the next article we choose to focus on is by Berte et al entitled a New Cryo-energy for Ventricular Tachycardia Ablation a Proof of Concept Study published in this past month's edition of Europace. One of the key problems in ventricular tachycardia ablation is the lack of transmural lesion formation. This is an important determinant of arrhythmia recurrence. Thus the group decided to do a proof of concept study to evaluate the safety and efficacy of a new and more powerful cryoablation system for ventricular ablation. They demonstrated that a novel cryoablation system to create large transmural ventricular lesions, whether it delivered by endocardial or epicardial approach. It was felt that this technology can hold potential for both surgical and catheter-based VT ablation in humans.                                                 While primarily studied in sheep models, it nevertheless highlights the importance of novel therapies that might better achieve through and through lesions. There are many different novel products being developed for the hope of achieving transmural lesions partly to target the myocardial circuits and partly to ensure achievement of through and through lesions without leaving residual potential substrate, because of only partial thickness lesions. These include things like needle ablation catheters, the safety of which still has to be fully evaluated, bipolar ablation or the use of technology such as novel cryo-energy approaches. Comparative efficacy of these different approaches however will be critical to determining which one is safest and best in any given clinical situation.                                                 Next we’ll review the article by Venlet et al published this past month's issue of Circulation Arrhythmia and Electrophysiology entitled Unipolar Endocardial Voltage Mapping in the Right Ventricle: Optimal Cutoff Values Correcting for Computed Tomography-derived Epicardial Fat Thickness and their clinical value for substrate delineation. The work by [inaudible 00:53:37] and others highlighted the importance of using unipolar and bipolar voltage cutoffs and helping delineate areas of both endocardial as well as potentially more distal such as epicardial scar during endocardial mapping. It is felt the low endocardial unipolar voltage during bipolar voltage mapping endocardially may indicate epicardial scar.                                                 However, the primary issues, the additional presence of epicardial fat both in the right ventricle and left ventricle and how this epicardial fat may effect normal unipolar voltage cutoffs. Thus, Venlet et al decided to review using computed tomography data the effective epicardial fat on unipolar voltage cutoffs. They demonstrated that endocardial unipolar voltage cutoff of 3.9 millivolts was more accurate than previously reported cutoff values for right ventricular epicardial scar during endocardial mapping.                                                 It was further demonstrated that while epicardial abnormal electrograms may be associated with transmural scar when associated with low endocardial bipolar voltage, the additional use of endocardial unipolar voltage and normal bipolar voltage sites can improve the diagnostic accuracy resulting in identification of all epicardial abnormal electrograms at sites with less than 1 mm of fat. Thus, the unipolar voltage not only assisted in evaluating whether epicardial scar was present, but also in further clarifying epicardial abnormal electrograms in terms of whether or not they truly represented potential transmural scar.                                                 Finally, within the realm of electrogram mapping of ventricular arrhythmias, we focus on the article by Magtibay et al entitled Physiological Assessment of Ventricular Myocardial Voltage using Omnipolar Electrograms published in the Journal of the American Heart Association this past month. Bipolar electrograms are traditionally used to characterize myocardial health. However, dependence on these electrograms may reduce the reliability of voltage assessment along different planes of arrhythmic myocardial substrates.                                                 Thus, newer catheters rely on evolving tools that might allow for different approaches to bipolar mapping. Using omnipolar electrograms, Magtibay et al studied in healthy rabbits, pigs and diseased humans under paced conditions the role of two bipolar electrode orientations both horizontal and vertical. Voltage maps were created for both bipoles and omnipoles, and they noted that electric orientation affected the bipolar voltage map with an average absolute difference between horizontal and vertical of up to 0.25 millivolts in humans. Thus, they demonstrated omnipoles can provide physiologically relevant and consistent voltages along the maximal bipolar direction and provide an advantage over traditionally obtained bipolar electrograms.                                                 When we consider the use of evolving techniques to get an understanding of myocardial health whether for the purpose of cardiac mapping and ablation or even for the purpose of other intervention such as cardiac biopsy, understanding what the voltage abnormalities perceived actually are is critical to understanding what substrate is actually being targeted. However, given directionality issues in terms of assessment of voltage as well as relative orientation of the catheter in understanding the relevance of received voltage, use of novel signal processing and electro designs are important to consider in the light of their effects on substrate mapping compared to traditional techniques.                                                 Changing gears yet again, but nevertheless related to cardiac mapping and ventricular arrhythmias, we focus on article by Yalagudri et al published in this past month's issue of the Journal of Cardiovascular Electrophysiology entitled A Tailored Approach for Management of Ventricular Tachycardia in Cardiac Sarcoidosis. While in a small number of patients, nearly 14 patients, they attempt to develop a methodology for approaching patients with cardiac sarcoidosis for management of their ventricular arrhythmias. Patients with either cardiac myocarditis or cardiac sarcoidosis represent a particularly difficult cohort to treat.                                                 Prior work by Dr. Roderick Tung and others has demonstrated the high-frequency of perceived inflammatory abnormalities based on cardiac FDG PET scanning amongst patients with ventricular arrhythmias. Whether this reflects cardiac sarcoidosis or other hypermetabolic activity is unclear. However, how to take into account the FDG PET abnormalities when deciding whether or not to take a patient for ablation or how to best treat them in light of their primary disease process is critical.                                                 In this study, the group tried to tailor therapy for ventricular tachycardia and cardiac sarcoidosis according to the phase of disease results. Namely based on the degree of inflammation noted on the FDG PET scan. They noted that via their named clinical protocol, that this tailored therapy could result in good clinical outcome and avoid unnecessary immunosuppression in some patients. Whether or not the use of this tailored therapy approach may apply in larger populations remains to be seen.                                                 Finally within the realm of other EP concepts that might apply broadly across the electrophysiology landscape, we focus on two articles. The first is by Kudryashova et al entitled Virtual Cardiac Monolayers for Electrical Wave Propagation in Nature Scientific Reports this past month. It is the complex structure of cardiac tissue that is considered to be one the main determinants of whether a substrate becomes arrhythmogenic or not. Multiple mathematical and computational models have been developed in order to recapitulate this complex cardiac structure. However, there been varying degrees of limitations in these approaches.                                                 Using a joint in silico-in vitro approach, the group carefully characterized the morphology of cardiac tissue and cultures of neonatal rat ventricular cells and then proposed mathematical models to result in tissue morphology that could be recapitulated for virtual studies of cardiac electrophysiology mainly in order to study wave propagation. They demonstrated in their virtual cardiac monolayers, that the simulated waves had the same anisotropy ratios and wave form complexity as those in in vitro experimental models.                                                 Thus, they demonstrated that they could reproduce both the morphological and physiological properties of cardiac tissue in a virtual landscape. These findings are critical to improving the ability to better study the effects of different antiarrhythmic drugs or interventional techniques on overall cardiac electrophysiology. The difficulty in existing techniques using traditional in vitro cultures is the fact that they’re costly and requires sacrifice of animals that adds to the additional cost of routine studies. The ability to recapitulate actual hearts within a virtual landscape to mimic the cardiac electrophysiology and then study it in a more controlled setting that can be reproducible based on the availability of appropriate computing power is important in terms of future studies within the realm of our field.                                                 The final article we will review is by Das and Dutta published in Physical Review E this past month entitled Controlling Three-Dimensional Vortices using Multiple and Moving External Fields. One of the key studies over the course of the last several years has been that of the role of the spiral and scroll waves in not just atrial fibrillation but ventricular fibrillation and other arrhythmias. It is well recognized that the spiral or scroll waves depending on whether one thinks in a two dimensional or three dimensional substrate may have significant contribution to arrhythmogenesis. Whether targeting the spiral or scroll waves actually eliminates arrhythmias remains to be fully elucidated. However, it also remains to be elucidated exactly how one should control the spiral or scroll waves.                                                 The review by Das and Dutta demonstrated that in fact the spiral or scroll waves could actually be physically moved around and controlled using moving external electric fields and thermal gradients. They show that the scroll rings can be made to trace cyclic trajectories on a rotating electric field or that application of thermal gradients in addition to electric field could deflect the motion and change the nature of a trajectory of a spiral or scroll wave. These findings are important in that they might represent non-ablative techniques that can eventually be used to control spiral or scroll waves in cardiac media, and thus result in either their alteration or termination without the need for additional cardiac injury.                                                 One the biggest problems with additional cardiac ablation in cases such as atrial fibrillation is the fact that they often lead to additional regions of scarring that might lead towards further organized atrial arrhythmias. However, the ability to potentially terminate critical sites responsible for arrhythmogenesis in real time without the need for ablation may represent novel interventions or devices in the future.                                                 I appreciate everyone's attention to these key and hard-hitting articles that we have just focus on from this past month of cardiac electrophysiology across the literature. Thanks for listening. Now back to Paul. Dr. Paul Wang :                 Thanks Suraj. You did a terrific job surveying all journals for the latest articles on topics of interest in our field. There is not an easier way to stay in touch with the latest advances. These summaries and a list of all major articles in our field each month could be downloaded from the Circulation: Arrhythmia and Electrophysiology website. We hope that you’ll find the journal to be the go to place for everyone interested in the field. See you next month.

Prof Le Gouill (University Hospital of Nantes, Nantes, France) and Prof Rule (Derriford Hospital, Plymouth, UK) review the data and opinions arising from ASH 2015 about the treatment of mantle cell lymphoma (MCL) for ecancertv. The two experts consider a range of topics including the place of new agents with the best combinations and sequences for utilising them. The predictive power of FDG-PET parameters at diagnosis and after patients with MCL interim results from the LyMa-PET project. They discuss ibrutinib versus temsirolimus and the results from a phase III, international, randomised, open-label, multicentre study in patients with previously treated mantel cell lymphomas. They also consider the potential role of MRD status as a prognostic marker for MCL in the future.

Dr Borchmann speaks at an EHA 2017 press session about the German Hodgkin Study Group HD18 trial to establish non-inferiority of PET guided chemotherapy for 4 cycles compared to current 8 week schedules. He describes how, at 5 years, PFS, OS and toxicity profiles all favour the reduced fraction, with only 2 of 500 patients developing a secondary lesion and improved quality of life for many patients. With the 4 cycle regimen proving at least as good as 8 cycles, Dr Borchmann encourages this as the new standard for advanced Hodgkin lymphoma in patients under 60.

Part 3 of my interview with Daniel Claasen, MD Dr. Daniel Claassen is an Assistant Professor of Neurology at Vanderbilt University and a neurologist specializing in the care of patients with neurodegenerative disorders, with particular interest in patients with cognitive dysfunction and movement disorders. He earned his medical degree from the Medical College of Georgia and completed his Neurology residency training at the Mayo Clinic, in Rochester, MN and postdoctoral training at the University of Virginia, in Charlottesville, VA. He is a past recipient of the American Academy of Neurology clinical research training grant. Dr. Claassen’s research focuses on understanding brain-behavior relationships in the context of the diagnosis and treatment of neurodegenerative diseases. Since 2009, he has focused his research efforts on behavioral studies in neurodegenerative disorders, evaluating the influence of medications on behavior and cognition. His current studies address cognitive changes that account for impulsive compulsive behaviors. Furthermore, he maintains an active clinical and research interest in the utility of functional neuroimaging. Clinically, his expertise in FDG PET quantitation enables improved recognition and diagnostic certainty of neurodegenerative disorders, such as Alzheimer’s disease.

Do you or a loved one deal with Huntington's disease?This is part one of my interview with Dr. Daniel Claassen, asst. professor of Neurology, Vanderbilt University.Dr. Daniel Claassen is an Assistant Professor of Neurology at Vanderbilt University and a neurologist specializing in the care of patients with neurodegenerative disorders, with particular interest in patients with cognitive dysfunction and movement disorders. He earned his medical degree from the Medical College of Georgia and completed his Neurology residency training at the Mayo Clinic, in Rochester, MN and postdoctoral training at the University of Virginia, in Charlottesville, VA. He is a past recipient of the American Academy of Neurology clinical research training grant. Dr. Claassen’s research focuses on understanding brain-behavior relationships in the context of the diagnosis and treatment of neurodegenerative diseases. Since 2009, he has focused his research efforts on behavioral studies in neurodegenerative disorders, evaluating the influence of medications on behavior and cognition. His current studies address cognitive changes that account for impulsive compulsive behaviors. Furthermore, he maintains an active clinical and research interest in the utility of functional neuroimaging. Clinically, his expertise in FDG PET quantitation enables improved recognition and diagnostic certainty of neurodegenerative disorders, such as Alzheimer’s disease

Part 2 of my interview with Daniel Claasen, MD Dr. Daniel Claassen is an Assistant Professor of Neurology at Vanderbilt University and a neurologist specializing in the care of patients with neurodegenerative disorders, with particular interest in patients with cognitive dysfunction and movement disorders. He earned his medical degree from the Medical College of Georgia and completed his Neurology residency training at the Mayo Clinic, in Rochester, MN and postdoctoral training at the University of Virginia, in Charlottesville, VA. He is a past recipient of the American Academy of Neurology clinical research training grant. Dr. Claassen’s research focuses on understanding brain-behavior relationships in the context of the diagnosis and treatment of neurodegenerative diseases. Since 2009, he has focused his research efforts on behavioral studies in neurodegenerative disorders, evaluating the influence of medications on behavior and cognition. His current studies address cognitive changes that account for impulsive compulsive behaviors. Furthermore, he maintains an active clinical and research interest in the utility of functional neuroimaging. Clinically, his expertise in FDG PET quantitation enables improved recognition and diagnostic certainty of neurodegenerative disorders, such as Alzheimer’s disease.

Thu, 13 Feb 2014 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16777/ https://edoc.ub.uni-muenchen.de/16777/1/Haslbeck_Marianne.pdf Haslbeck, Marianne ddc:610, ddc:600, Medizi

Breast Cancer

Background: Earlier functional imaging studies on visually induced self-motion perception (vection) disclosed a bilateral network of activations within primary and secondary visual cortex areas which was combined with signal decreases, i.e., deactivations, in multisensory vestibular cortex areas. This finding led to the concept of a reciprocal inhibitory interaction between the visual and vestibular systems. In order to define areas involved in special aspects of self-motion perception such as intensity and duration of the perceived circular vection (CV) or the amount of head tilt, correlation analyses of the regional cerebral glucose metabolism, rCGM (measured by fluorodeoxyglucose positron-emission tomography, FDG-PET) and these perceptual covariates were performed in 14 healthy volunteers. For analyses of the visual-vestibular interaction, the CV data were compared to a random dot motion stimulation condition (not inducing vection) and a control group at rest (no stimulation at all). Results: Group subtraction analyses showed that the visual-vestibular interaction was modified during CV, i.e., the activations within the cerebellar vermis and parieto-occipital areas were enhanced. The correlation analysis between the rCGM and the intensity of visually induced vection, experienced as body tilt, showed a relationship for areas of the multisensory vestibular cortical network (inferior parietal lobule bilaterally, anterior cingulate gyrus), the medial parieto-occipital cortex, the frontal eye fields and the cerebellar vermis. The "earlier" multisensory vestibular areas like the parieto-insular vestibular cortex and the superior temporal gyrus did not appear in the latter analysis. The duration of perceived vection after stimulus stop was positively correlated with rCGM in medial temporal lobe areas bilaterally, which included the (para-) hippocampus, known to be involved in various aspects of memory processing. The amount of head tilt was found to be positively correlated with the rCGM of bilateral basal ganglia regions responsible for the control of motor function of the head. Conclusions: Our data gave further insights into subfunctions within the complex cortical network involved in the processing of visual-vestibular interaction during CV. Specific areas of this cortical network could be attributed to the ventral stream ("what" pathway) responsible for the duration after stimulus stop and to the dorsal stream ("where/how" pathway) responsible for intensity aspects.

Aims: In this study, we aimed to compare cerebrospinal fluid (CSF) levels of total tau (t-tau), phosphorylated tau (p-tau(181)) and positron emission tomography with F-18-fluorodeoxyglucose (FDG-PET) in the differential diagnosis of Alzheimer's disease (AD) under clinical conditions. Method: In a cross-sectional, blinded, single-center study, we examined a sample of 75 unselected memory clinic patients with clinical diagnoses of dementia of Alzheimer type (DAT; n = 24), amnestic mild cognitive impairment (MCI; n = 16), other dementias (n = 13) and nondemented controls (n = 22). Discriminative accuracy, sensitivity and specificity were calculated and compared using ROC analyses. Results: p-tau(181) and FDG-PET were comparable in separating DAT from controls (sensitivity: 67 vs. 79%; specificity: 91% for both) and patients with other dementias (sensitivity: 71 vs. 79%; specificity: 100% for both). The sensitivity of p-tau 181 in differentiating MCI patients from controls was significantly (p < 0.05) superior to that of FDG-PET (75 vs. 44%) at a comparably high specificity (82 vs. 91%); t-tau measures were less accurate in all analyses. Conclusions: FDG-PET and CSF p-tau(181) levels are able to discriminate DAT in heterogeneous and unselected samples with a high accuracy. CSF p-tau(181) might be somewhat superior for a sensitive detection of patients with MCI. Copyright (C) 2010 S. Karger AG, Basel

Demenz ist ein Syndrom, das durch einen Verlust der kognitiven Funktionen wie Gedächtnis, Orientierung und Denken sowie eine Beeinträchtigung der Alltagsrelevanz charakterisiert ist. Patienten mit einer Demenz zeigen ein regionales Defizit des Glucosemetabolismus im Gehirn. Das Ziel dieser Studie ist, einen Zusammenhang zwischen der neuropsychologischen Untersuchung und des regionalen Glucosemetabolismus des Gehirns bei Demenz-Patienten zu finden. In dieser Studie wurden 24 Patienten mit einer Demenz im Alter 69.2  7.5 Jahren, die nach den Kriterien der ICD-10 und der DSM-IV diagnosziert wurden, eingeschlossen. Die kognitiven Leistungen wurden mit Hilfe der CERAD-NP Testbatterie, des Uhrentests nach Shulman und des Stroop-Paradigmas nach dem Nürnberger-Alters-Inventar (NAI) getestet. Die MRT- und FDG-PET Untersuchungen wurden bei allen Patienten durchgeführt. Die Bildgebungsdatensätze wurden mit Hilfe der Medical Image Processing, Analysis and Visualisation software (MIPAV) nach der Region of Interest (ROI) – Methode in neun Gehirnregionen (die rechten und linken Hemisphären, der rechte und linke Gyrus frontalis inferior, der rechte und linke Hippocampus, der rechte und linke Parietallappen) ausgewertet. Die Daten wurden mittels des Spearman-Koeffizierten korreliert. In dieser Studie wurde eine signifikante Korrelation zwischen dem MMSE–Wert und dem Hypometabolismus im linken und rechten Parietallappen ermittelt. Beeinträchtigungen in der verbalen Lernleistung (Wortliste Lernen im CERAD-NP) korrelierten mit einem Hypometabolismus in der linken Hemisphäre, dem linken und rechten Hippocampus und dem linken Parietallappen. Zusätzlich wurde eine signifikante Korrelation zwischen der Wortliste Wiedererkennen (CERAD-NP) und einem reduzierten zerebralen Metabolismus des linken Gyrus frontalis inferior gefunden. Die konstruktive Praxis (CERAD-NP) korrelierte mit einem verringerten Glukosemetabolismus in der rechten Hemisphäre. Die visuokonstruktive Praxis (Uhrentest) konnte nicht signifikant mit spezifischen Gehirnregionen in Verbindung gebracht werden. Auffälligkeiten im Stroop-Paradigma korrelierten mit einem Hypometabolismus im rechten Gyrus frontalis inferior. Die Ergebnisse dieser Studie zeigen, dass spezifische kognitive Defizite Aufschluss über die entsprechende Lokalisation der neurodegenerativen Erkrankung im Gehirn geben können.