Podcasts about Doxorubicin

Medicus Pharma CEO Dr Raza Bokhari joined Steve Darling from Proactive to announce the submission of a comprehensive product development plan to the U.S. FDA for the treatment of external squamous cell carcinoma (SCC) in horses. The submission was made under the Investigational New Animal Drug (INAD) program and seeks concurrence under the Minor Use in Major Species (MUMS) designation. The FDA recently granted MUMS designation to Medicus Pharma's dissolvable Doxorubicin-containing microneedle array, which is specifically designed to treat external SCC in equine patients. This recognition enables the company to pursue regulatory pathways designed to support treatments for rare conditions in major animal species. Dr. Bokhari explained that SCC is a skin tumor commonly affecting adult or aging horses with white or partially white coats. Breeds such as Appaloosa, Belgian, American Paint, and Pinto are particularly vulnerable. The incidence of SCC in horses is estimated at 2-3%, with the U.S. horse population currently ranging from 6.6 to 7.25 million animals. Current treatment options involve surgical removal of larger tumors, cryotherapy for smaller lesions, and localized or topical chemotherapy. Some cases are also managed with oral medications like piroxicam to slow cancer recurrence. Bokhari noted that the company's microneedle platform could offer a less invasive and more targeted treatment alternative. With the development plan now submitted, Medicus Pharma is aiming to align with the FDA on next steps to bring this innovative treatment to market, providing a new option for veterinarians and horse owners dealing with equine SCC. #proactiveinvestors #nasdaq #mdcx #tsxv #mdcx #pharma #Biotech #CancerTreatment #ClinicalTrials #FDAApproval #SkinCancer #HealthcareInnovation #Investing #MedicalResearch #SkinCancer #BasalCellCarcinoma #BiotechNews #CancerResearch #UAEHealth #NonInvasiveTherapy #Doxorubicin #ClinicalTrials #HealthcareInnovation VeterinaryOncology #HorseCancer #SquamousCellCarcinoma #FDAApproval #AnimalHealth

Commentary by Dr. Alexander Maass.

BELIEVING IN HOPE WITHOUT COMPROMISE. Dr Virgilio Sacchini is dedicated to caring for people with breast cancer at the Memorial Sloan Kettering Cancer Center in New York. He originally trained at Universita degli Studi di Milano (UNIMI, Milan, Italy) where he is Professor of Surgery, and cooperates with the European Institute of Oncology in Milan (IEO, Milan, Italy). Dr Sacchini is a 2023 and 2024 Castle Connolly America's Top Doctor, the peer nominated group of the top 7% of all US practicing physicians. His goal is to achieve the best possible cancer outcomes and cosmetic results for his patients. “The new concept is to target only cancer cells.” “To cure someone and give him or her a miserable life is terrible, so the target in this moment is both better survival and better quality of life, less side effects.” “Once we prove that the combination of the medication with the Avacta technique works, of course it is approved and you can be cured everywhere in the world.”

LMS04 final OS results are published for doxorubicin + trabectedin in Leiomyosarcoma. Plus, a natural experiment of what happens in small cell lung cancer during an IV etoposide shortage. Finally, a nice paper provides some examples of how oncology pharmacists can bridge the care gap between oncology and primary care. LMS04: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2403394 IV etoposide shortage: https://doi.org/10.1200/OP.24.00394 Primary care - oncology pharmacy collaboration: https://doi.org/10.1177/10781552241279303

Today we feature "Doxorubicin: Infusion" by Laura Paul Watson Please send your submissions to be featured on the podcast to poetryinmedicine@gmail.com. "In whatever you do, read a poem." Honored to have been named one of the top 10 medical podcasts in the state of Georgia by Feedspot: podcasts.feedspot.com/georgia_medical_podcasts/

By Laura Paul Watson

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial" by Camus et al published February 16th, 2024 and the associated editorial written by Dr. Mehta-Shah and Dr. Horwitz. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing a clinical trial update published in the May 10th issue of JCO addressing the long term follow up of the addition of romidepsin to CHOP chemotherapy for previously untreated peripheral T-cell lymphoma, or PTCL. This report by Camus et al discusses a five-year follow up of the original Ro-CHOP trial, which did not meet its primary endpoint of progression free survival. The original Ro-CHOP study, conducted by the LYSA group, was published in 2021 in JCO and was conducted as a one-to-one randomized phase III study of Ro-CHOP versus CHOP for patients aged 18 to 80 years with PTCL. 98 international centers were included, and the study enrolled patients between 2013 and ‘17. Nodal follicular helper T-cell, or TFH lymphoma was defined in this study follow-up as a PTCL expressing at least two of five TFH markers according to the latest classifications. The study's primary endpoint was PFS with secondary endpoints of OS and duration of response, or DOR. Five year follow up was reached in December 2022. In the original study report, the addition of romidepsin to CHOP did result in a reduction of dose intensity of chemotherapy. However, in this updated follow up, there were no new safety signals reported. A total of 421 patients were enrolled in the trial with a median age of 65 years. Notably, those who were randomized to the Ro-CHOP arm had a higher proportion of IPI 4-5 scores at 33%, versus 24% of those who were assigned to CHOP alone despite randomization. Nearly half of patients carried a histologic diagnosis of angioimmunoblastic T-cell lymphoma. 30% were characterized as PTCL NOS, not otherwise specified, 10% ALK negative anaplastic large cell lymphoma, leaving 13% reported as other. Over 60% of patients had stage four disease at enrollment, with nearly half having more than two sites of extranodal involvement. Median follow up was six years with a median PFS of 12 months for Ro-CHOP and 10.2 months for CHOP, which did not reach statistical significance as reported in the original study publication. Estimated five year OS available as a part of this clinical trial update was 50% for Ro-CHOP and 43% for CHOP alone, and also did not reach significance. There was, however, a longer duration of response observed in the Ro-CHOP arm at 52 months versus 24 months for CHOP, which is a new finding in this extended follow up of the study. In an effort to better understand whether there are subgroups which may benefit from romidepsin despite the overall negative outcome of this study, the authors are able to provide new insights from this Ro-CHOP study in line with our current and updated understanding of PTCL. When the authors evaluated the study population for subgroups which may benefit from addition of romidepsin, TFH lymphomas, which included angioimmunoblastic, follicular, and NOS subtypes, were noted to have an improved response to the addition of this HDAC inhibitor. This subgroup, numbering 201 patients, experienced a mean PFS of over 19 months with Ro-CHOP versus over 10 months for those who received CHOP, and this difference achieved statistical significance. Similarly, there was a higher complete response rate and longer duration of response for those in the TFH subgroup who received romidepsin. The authors also make note that those patients in this subgroup with high IPI appeared to particularly benefit. However, those in the PTCL NOS group who did not fit the TFH subtype experienced poor outcomes with shorter PFS and OS as compared to other histologic subtypes, which is in line with other reported data in the field. The authors in this update also report on treatments and outcomes after first progression or relapse of disease, which includes a total of 274 patients, of whom 251 received second line therapy. The median PFS in OS after progression or relapse was only 3.3 months and 11.5 months, respectively, and again, patients with the TFH subtype experienced a longer median OS than other included histologies. Only 8% of patients proceeded to undergo autologous stem cell transplantation overall, and 5% underwent allogeneic stem cell transplantation. While the authors note that they did not observe any notable outcome differences between various included second line therapies, they do note of a possible benefit of the antibody drug conjugate brentuximab vedotin or BV in combination with chemotherapy backbones. Those who received a BV containing regimen in the second line experienced a better CR rate and a longer PFS, too. However, the OS too was not significantly different. Again, the authors note that most of the benefit of the addition of BV to chemotherapy in the second line appeared focused on this TFH lymphoma subgroup. Of note, CD30 status was not recorded as a part of the study for included patients and could not be further reported on. The findings of the authors present in this subgroup analysis of the negative Ro-CHOP study seek to find benefit in future lessons for patients with these rare lymphomas who do not have a multitude of effective treatments available to them. The subgroup benefit in this clinical trial update based on the TFH phenotype fits our evolving understanding of PTCL in the modern era. Mutations characteristic of the TFH subgroup, in this case often involved in chromatin modification and the tumor microenvironment, have been linked to improved responses when treating with epigenetic targeting drugs such as romidepsin, thus making the findings of TFH lymphoma in the Ro-CHOP trial confirmatory of what we would expect from correlative studies. Despite the benefit of Ro-CHOP for those with TFH lymphoma, this updated analysis of a major frontline study of PTCL highlights the critical need in the T-cell lymphoma field to, first of all, better understand and separate what we have come to recognize as the heterogeneous diseases historically lumped together as PTCL. This historic classification, based on a lack of deeper molecular understanding of disease biology is unlikely to represent the true biologic diversity of its component subtypes, including the focus on TFH lymphoma presented here. The second critical unmet need, which this subgroup analysis highlights, is the need to investigate the benefit of new therapeutic agents in these distinct subgroups of PTCL, where the need for improved survival outcomes is sorely needed when examining historical outcomes with currently available therapies, both in the frontline setting as well as those in the relapsed refractory group. The associated editorial, written by Dr. Mehta-Shah and Dr. Horwitz, elegantly discusses the challenges of designing studies in rare diseases such as PTCL, which are both biologically informed as well as appropriately powered. As the authors discuss, it is rare to get a second chance for a drug, as is the case for romidepsin, where these negative results led to its voluntary withdrawal in PTCL, affecting availability of the drug for patients in the relapsed setting, as well as future clinical trials, which could have had potential for success. Additionally, better understanding of the biological underpinnings of PTCL needs to lead to better designed and appropriately powered clinical trials, as these subsets of patients are in great need of therapeutic advances. While none of these tasks is easy nor straightforward, this clinical trial update of the RoCHOP study suggests a path forward from learning from prior, promising yet failed attempts at moving the standard of care for frontline therapy of T-cell lymphoma forward. This is Alexandra Rojek thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascp.org/podcasts. 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.  

Upon diagnosing acute myeloid leukemia (AML), the initial step involves assessing a patient's eligibility for intensive chemotherapy. The standard treatment protocol for newly diagnosed AML encompasses intensive chemotherapy to achieve complete remission, followed by post-remission therapy, which may include additional chemotherapy and/or stem cell transplantation. Complete response rates to this approach range from 60% to 85% in adults aged 60 or younger. While this approach has proven effective, the risk of relapse within three years of diagnosis remains a significant concern. Numerous factors contribute to the likelihood of relapse, including short duration of remission, genetic derangements, prior allogeneic transplantation, advanced age, and concomitant comorbidities. These negative prognostic factors underscore the need for continuous exploration of novel therapeutic agents, as relapse remains a formidable barrier to treatment success. In a new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally (awarded the Nobel Prize in Physiology or Medicine in 1977), and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami, investigated newly emerging therapies targeting drug resistance in AML. On April 8, 2024, their new research paper was published in Oncotarget's Volume 15, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.” Full blog - https://www.oncotarget.org/2024/05/23/combating-doxorubicin-resistant-acute-myeloid-leukemia/ Paper DOI - https://doi.org/10.18632/oncotarget.28579 Correspondence to - Simonetta I. Gaumond - sxg1204@miami.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28579 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, leukemia, AML, resistance, growth hormone-releasing hormone, MIA-602 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. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY- April 10, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on April 8, 2024, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.” Acute myeloid leukemia (AML) is characterized by the rapid proliferation of mutagenic hematopoietic progenitors in the bone marrow. Conventional therapies include chemotherapy and bone marrow stem cell transplantation; however, they are often associated with poor prognosis. Notably, growth hormone-releasing hormone (GHRH) receptor antagonist MIA-602 has been shown to impede the growth of various human cancer cell lines, including AML. In this new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally, and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant AML cell lines, KG-1A, U-937, and K-562. “Given the role of GHRH in multiple cancer types, it is possible that GHRH antagonists may offer an alternative treatment approach for AML as well as drug-resistant AML, which may circumvent the side effects associated with standard chemotherapy.” The in vitro results revealed a significant reduction in cell viability for all treated wild-type cells. Doxorubicin-resistant clones were similarly susceptible to MIA-602 as the wild-type counterpart. Their in vivo experiment of xenografted nude mice with Doxorubicin-resistant K-562 revealed a reduction in tumor volume with MIA-602 treatment compared to control. “Our study demonstrates that these three AML cell lines, and their Doxorubicin-resistant clones, are susceptible to GHRH antagonist MIA-602.” DOI - https://doi.org/10.18632/oncotarget.28579 Correspondence to - Simonetta I. Gaumond - sxg1204@miami.edu Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, leukemia, AML, resistance, growth hormone-releasing hormone, MIA-602 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. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Commentary by Dr. Nazish Sayed

“The search for daunorubicin's sister really led to this discovery of doxorubicin, which is an analog with much greater activity. The discovery of doxorubicin can be coined kind of as, ‘one of the best drugs born in Milan, Italy.' And after that, a few analogs were developed and tested, and two that we currently use today, are idarubicin and epirubicin,” Puja Patel, PharmD, BCOP, clinical oncology pharmacist at the Delnor Hospital Northwestern Medicine Cancer Center in Geneva, IL, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a discussion about anthracyclines and other antitumor antibiotics. This episode is part of a series about drug classes, which we'll include a link to in the episode notes.  You can earn free NCPD contact hours after listening to this episode and completing the evaluation linked below.   Music Credit: “Fireflies and Stardust” by Kevin MacLeod  Licensed under Creative Commons by Attribution 3.0  Earn 0.75 contact hours of nursing continuing professional development (NCPD), which may be applied to the nursing practice, oncology nursing practice, symptom management, palliative care, supportive care, or treatment ILNA categories, by listening to the full recording and completing an evaluation at myoutcomes.ons.org by January 26, 2026. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of NCPD by the American Nurses Credentialing Center's Commission on Accreditation.  Learning outcome: The learner will report an increase in knowledge of anthracyclines and antitumor antibiotics.  Episode Notes  Complete this evaluation for free NCPD.   Oncology Nursing Podcast: Pharmacology 101 series  ONS Voice oncology drug reference sheets  IV Cancer Treatment Education Sheets  ONS Voice articles:  The Evidence Is Building for ACE Inhibitors in Anthracycline-Associated Cardiotoxicity  Outpatient Oncology Drug Series: Doxorubicin Is the Infamous Red Devil  Clinical Journal of Oncology Nursing articles:  Nursing Alchemy: Transforming R-CHOP Information Into Essentials  Dyspnea: Common Side Effect  Cardiac Toxicity: Using Angiotensin-Converting Enzyme Inhibitors to Prevent Anthracycline-Induced Left Ventricular Dysfunction and Cardiomyopathy  Oncology Nursing Forum article: Symptom Clusters in Lymphoma Survivors Before, During, and After Chemotherapy: A Prospective Study  ONS Huddle Card: Antitumor Antibiotics  Additional healthcare professional resources:  Blindspot: Hidden Biases of Good People  Harvard University Implicit Association Test  OncoPharm Podcast  ASCO Education Podcast  Additional patient resources:  National Comprehensive Cancer Network patient resources  National Comprehensive Cancer Network patient webinars  National Cancer Institute resources for patients   To discuss the information in this episode with other oncology nurses, visit the ONS Communities.   To find resources for creating an ONS Podcast Club in your chapter or nursing community, visit the ONS Podcast Library.  To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org.  Highlights From Today's Episode  “Anthracyclines are kind of categorized as topoisomerase II inhibitors, and these agents are very powerful in that they have—it's really like three drugs in one—they have various mechanisms.” TS 3:55  “We need to create a stable environment, and so we actually cut one of the cords, and that's exactly what topoisomerase is doing. It's cutting one of the DNA strands. And in this case, it's cutting two strands, and that's why it's called topoisomerase II, so it's cutting both of the strands. It's cutting the DNA, releasing some of that tension, allowing for replication, and then rejoining that portion. So, it's a very important enzyme, and it'll go about doing this for the entire strand of DNA.” TS 4:50  “The other second mechanism is kind of the effect on DNA. So, you'll come across reading the term ‘DNA intercalation.' So, what does that word mean? When you take the word ‘intercalate,' the definition of it means ‘intrusive inserting of something in an existing series or sequence.' The analogy that I could think of here is simple: It's thinking about too many passengers squeezing in the backseat of your car. There could be safety issues, there's weight issues, there's instability maybe while driving. And that's what this doxorubicin is doing. It's sliding right in between the base pairs of the DNA double helix, destroying hydrogen bonds between those two bases, which then change the shape of that double helix. And by changing the shape, topoisomerase II, which we just talked about, can no longer go in and bind to DNA. It can't relax that super coil. And so, DNA synthesis doesn't happen.” TS 6:02  “So, the main toxicity that our listeners might be familiar with is cardiotoxicity. And also with cardiotoxicity, breaking it down a little bit, there's an onset that occurs during treatment or even years to decades, and that's kind of this delayed cardiotoxicity. Signs and symptoms of acute cardiotoxicity could vary from EKG changes present as tachycardia, tachyarrhythmia. Delayed cardiotoxicity is anything from heart failure to left ventricular ejection fraction decrease.” TS 9:41  “We're worried about heart failure in these patients. So, we might see EKG changes, we might see LVEF [left ventricular ejection fraction] changes, and we're kind of tracking these agents based on what is called cumulative dose tracking or lifetime dose. So, all of these agents have specific lifetime maximums that we need to be aware of.” TS 14:53  “So, smoking, hypertension, diabetes, dyslipidemia, obesity, or you're older in age, or perhaps you have a compromised cardiac function—you're at greater risk for developing these cardiotoxicities. An example that I've had in my clinic is I've identified some of these patients that have these risk factors, and we go into a little bit more aggressive monitoring for the echocardiogram or MUGA [multigated acquisition]. And when we put in those orders, we often get denials from insurance. We submit the guidelines in, kind of, appeals to help those patients kind of proactively realize if we're putting them in a greater cardiac risk.” TS 15:47  “One of the biggest things is for nurses to kind of look over their policies for administration for vesicants and specifically checking blood return for these agents, because many of them are given, you know, IV push. So, checking blood return every 2–5 ml is really important to make sure that you are in the right space. And then these agents, some of them can also be given continuously. So, you're thinking about, first of all, you should have a central line in for these agents because they're vesicants. But if it's being given continuous, there is something that's called anthracycline streaking, and it's not the same as an extravasation. So, I think being able to decipher the difference between the two is really, kind of, comes with experience.” TS 20:36  “I think awareness is really essential. And thankfully, you know, thankfully or not, I guess, you were with the patient for this entire time, right? Because you're pushing every 2–5 ml, you're checking. So, it's a very kind of intimate experience in and of itself. So, I think just being very vigilant is very important.” TS 22:24  “So, to talk about bleomycin here, for example, kinetically, two-thirds of this drug is eliminated renally. And so, we would think that there would need to be renal adjustments if there's renal changes. So, for creatinine clearance greater than 50, there are no renal dose adjustments. But after that, every 10 ml per minute decrease in GFR [glomerular filtration rate], there are dose reductions that are required. And this drug, in particular, has a lot of gradations in terms of renal dysfunction that I've seen.” TS 27:30  “Thinking about bleomycin, it's IV over 10 minutes, and you want to think about the lifetime maximum dose. So, when you are working up your patient, that's something to kind of think about. Dactinomycin is highly emetogenic, so making sure that there's antibiotics on board. It's also a vesicant, so thinking about vesicants precautions. Cold compresses is how you would help treat that if there is an extravasation.” TS 33:14   “I think trust is the foundation oncology really because we are asking our patients to do so many things outside of our infusion center, picking up medications, taking medications, calling us about signs and symptoms, going and getting all these imaging know. So, if there isn't that foundation of trust, having this perfect curative treatment plan may be more challenging to really be carried out.” TS 38:06  “We've developed these very powerful agents, and they're non–cell specific. So, I think the next step would be, how can we reformulate them to make them less toxic and provide more of a targeted approach? And so, perhaps an antibody-drug conjugate that is specifically attacking the lymphoma or the breast cell can deliver this chemotherapy with a cytotoxic payload is there in the horizon.” TS 39:07  “I think the misconception that ‘I will develop heart damage' is really important. Doxorubicin has the infamous name of the red devil, but I think it's important to let your patients know that heart failure increases with cumulative dosing. You know, talking to them about 300 mg/m2 is associated with a 1.5% heart failure risk. Whereas going all the way across to 500 mg/m2, now you're looking at 6%–20% probability of developing heart failure.” TS 42:30  “I think taking the time and understanding the literature. Typically, we don't start these agents with LVEF less than 50–55. There's some great review articles in JCO [Journal of Clinical Oncology] that kind of define what cardiomyopathy decrease looks like and decreases in LVEF over 10% to a value below the institutional limit of normal, I think, is a nice point to have as a value, a number to kind of work with.” TS 43:53  “Working with your nurse educator and leader to help achieve OCN®, oncology certified nurse, certification is really important. And I think live simulated experiences are really beneficial, maybe even looking at extravasations or having an infusion-related reaction, because here in the acute setting, we're really kind of in this like responsive mode. But if we practice, we can respond more deliberately and more calmly.” TS 45:05 

This is the second of the three-part podcast series, Keeping up with the Chemos on Trabectedin and Doxorubicin. Our multidisciplinary panel will discuss the important information about the drug preparation and administration of Trabectedin and Doxorubicin. Focusing on oral dosing, infusion pump setup, lab examinations, and patient education. The session ends with general take home points on administration and toxicity prevention interventions.2023-2024 SGO Chemotherapy and Targeted Therapies Subcommittee Members and Moderators:Tracilyn Hall, MD Jennifer MacDonald, PharmD, BCOPSpeakers:Sminu Bose, MDJoshua Cohen, MD Claire Marie Mach, PharmD, BCOP    Sound engineered and produced by Betheon Whyte on behalf of the Society of Gynecologic Oncology. 

This is the last of the three-part podcast series, Keeping up with the Chemos on Trabectedin and Doxorubicin. Our multidisciplinary panel will discuss the challenges with patient monitoring while on Trabectedin and Doxorubicin. When to dose adjust and hold or even discontinue Trabectedin and Doxorubicin. Once again, the podcast ends with take home points for patient monitoring and side effects while on Trabectedin and Doxorubicin.  2023-2024 SGO Chemotherapy and Targeted Therapies Subcommittee Members and Moderators:Tracilyn Hall, MDJennifer MacDonald, PharmD, BCOPSpeakers:Sminu Bose, MDJoshua Cohen, MD Claire Marie Mach, PharmD, BCOP    Sound engineered and produced by Betheon Whyte on behalf of the Society of Gynecologic Oncology. 

This is the first of the three-part podcast series, Keeping up with the Chemos on Trabectedin and Doxorubicin. After going over some general information on Trabectedin and Doxorubicin including when to use the drug, checking patient performance status, toxicity, and line of therapy and treatment option for recurring metastasis disease. The multidisciplinary panel will discuss dosing and drug preparation for giving Trabectedin and Doxorubicin. The session wraps up with some key take home points on Trabectedin and Doxorubicin.  2023-2024 SGO Chemotherapy and Targeted Therapies Subcommittee Members and Moderators:Tracilyn Hall, MDJennifer MacDonald, PharmD, BCOPSpeakers:Sminu Bose, MDJoshua Cohen, MD Claire Marie Mach, PharmD, BCOP    Sound engineered and produced by Betheon Whyte on behalf of the Society of Gynecologic Oncology. 

A new research paper was published in Oncotarget's Volume 14 on July 1, 2023, entitled, “Transformation of immunosuppressive mtKRAS tumors into immunostimulatory tumors by Nerofe and Doxorubicin.” Members of the rat sarcoma viral oncogene (RAS) subfamily KRAS are frequently mutated oncogenes in human cancers and have been identified in pancreatic ductal, colorectal, and lung adenocarcinomas. Recently, two drugs that specifically target KRAS G12C, sotorasib (Lumakras™) and adagrasib (Krazati™), have received accelerated approval by the FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy. These drugs are the first RAS GTPase family inhibitors to be approved for clinical use, representing a major breakthrough in the field of precision oncology. In this new study, researchers Joel Ohana, Uziel Sandler, Orly Devary, and Yoram Devary from Immune System Key (ISK) and Jerusalem College of Technology show that a derivative of the hormone peptide Tumor Cell Apoptosis Factor (TCApF), Nerofe™ (dTCApFs), in combination with Doxorubicin (DOX) substantially reduces viability of tumor cells. “The objective of the present study was to investigate the synergistic effect of the combination of Nerofe and DOX in colorectal cancer and its underlying mechanism.” It was observed that the combination of Nerofe and DOX downregulated KRAS signaling via miR217 upregulation, resulting in enhanced apoptosis of tumor cells. In addition, the combination of Nerofe and DOX also resulted in activation of the immune system against tumor cells, manifested by an increase in the immunostimulatory cytokines IL-2 and IFN-γ as well as the recruitment of NK cells and M1 macrophages to the tumor site. “In conclusion, we demonstrated that the combination of Nerofe and DOX exerts a synergistic effect during mCRC treatment, which could stem from several independent and complementary mechanisms of action.” DOI - https://doi.org/10.18632/oncotarget.28467 Correspondence to - Yoram Devary - ydevary@immunesk.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28467 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - Colorectal cancer, KRAS, apoptosis, hormone peptide, endoplasmic reticulum stress About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Commentary by Dr.Giselle Melendez

Drs Sumanta Pal and Pavlos Msaouel discuss the unique pathophysiology of renal medullary carcinoma, treatment options, clinical trials, and the importance of screening and early detection. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/984239). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Renal Medullary Carcinoma and Its Association With Sickle Cell Trait: A Case Report and Literature Review https://pubmed.ncbi.nlm.nih.gov/32218668/ Renal Medullary Carcinoma: The Kidney Cancer That Affects Individuals With Sickle Cell Trait and Disease https://pubmed.ncbi.nlm.nih.gov/28697316/ Renal Medullary Carcinoma: A National Analysis of 159 Patients https://pubmed.ncbi.nlm.nih.gov/28485059/ Sickle Cell Trait https://pubmed.ncbi.nlm.nih.gov/30725815/ 2004 WHO Classification of the Renal Tumors of the Adults https://pubmed.ncbi.nlm.nih.gov/16442207/ Renal Cell Carcinoma Unclassified With Medullary Phenotype in a Patient With Neurofibromatosis Type 2 - PubMed (nih.gov) https://pubmed.ncbi.nlm.nih.gov/36975468/ Association of High-Intensity Exercise With Renal Medullary Carcinoma in Individuals With Sickle Cell Trait: Clinical Observations and Experimental Animal Studies https://pubmed.ncbi.nlm.nih.gov/34885132/ Metastatic Renal Medullary and Collecting Duct Carcinoma in the Era of Antiangiogenic and Immune Checkpoint Inhibitors: A Multicentric Retrospective Study https://pubmed.ncbi.nlm.nih.gov/35406448/ Ixazomib, Gemcitabine, and Doxorubicin in Treating Patients With Locally Advanced or Metastatic Kidney Cancer https://clinicaltrials.gov/ct2/show/NCT03587662 Phase II Trial of Immunotherapy in Patients With Carcinomas Arising From the Renal Medulla https://clinicaltrials.gov/ct2/show/NCT05347212

Our hosts Dr. Stephen Caselli and co-hosts Dr. Arjun K Ghosh and Dr. Daniel Lenihan are interviewing Dr. Tochukwu M. Okwuosa to discuss the following topic “Social disparities in Cardio-oncology care”. Dr. Okwuosa is a cardiologist and a professor of medicine at Rush University. She is the Director of Cardio-Oncology Services at Rush University Medical Center. She initiated and developed the cardio-oncology program at the Karmanos Cancer Center in Detroit and left shortly afterward to develop and build the now successful cardio-oncology program at Rush University Medical Center. Episode Pearls 1. The interplay of various socio-economic determinants has an impact on the clinical outcomes of cancer patients with co-existing cardiovascular diseases (CVD) 1 . Prior studies have shown that marrying both cancer and cardiovascular disease increases mortality, especially in counties with higher social vulnerability based on the social vulnerability index 2. 2. African Americans (AA) had a three times higher risk of developing cardiotoxicity with doxorubicin compared to non-AA patients, and in breast cancer patients receiving trastuzumab therapy, AA women had 4 times fold of developing cardiotoxicity compared to white women 3,4. 3. Healthcare accessibility is an important social determinant of health and a major factor in the healthcare gap between rural and urban regions worldwide. Cardio-oncology Clinics based on telehealth platforms might decrease the gap in providing cardio-oncology care 5 . 4. Raising awareness about Cardio-oncology and enhancing education is one of the pillars of decreasing social disparities among cancer patients. Establishing collaborative educational platforms such as the Chicago Citywide Cardio-Oncology Rounds (CCCR) helps to facilitate the exchange of clinical knowledge and scientific experience 6 . Reproducing such initiatives on a nationwide basis will help in eliminating geographical barriers to accessing cardio-oncology care. 5. Building registries collaboratively will help identify patients' social disparities such as Global Cardio-Oncology Registry (G-COR, ClinicalTrials.gov Identifier:NCT05598879). Another example is how building a registry for Immune checkpoint Inhibitors Myocarditis (ICI) has raised awareness about identifying patients presenting with ICI-myocarditis. References 1. Ahmad J, Muthyala A, Kumar A, Dani SS, Ganatra S. Disparities in Cardio-oncology: Effects On Outcomes and Opportunities for Improvement. Curr Cardiol Rep. 2022;24(9):1117-1127. doi:10.1007/s11886-022-01732-2 2. Ganatra S, Dani SS, Kumar A, et al. Impact of Social Vulnerability on Comorbid Cancer and Cardiovascular Disease Mortality in the United States. JACC CardioOncol. 2022;4(3):326-337. Published 2022 Sep 20. doi:10.1016/j.jaccao.2022.06.005 3. Hasan S, Dinh K, Lombardo F, Kark J. Doxorubicin cardiotoxicity in African Americans. J Natl Med Assoc. 2004;96(2):196-199. 4. Litvak A, Batukbhai B, Russell SD, et al. Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer. Cancer. 2018;124(9):1904-1911. doi:10.1002/cncr.31260 5. Kappel C, Rushton-Marovac M, Leong D, Dent S. Pursuing Connectivity in Cardio- Oncology Care-The Future of Telemedicine and Artificial Intelligence in Providing Equity and Access to Rural Communities. Front Cardiovasc Med. 2022;9:927769. Published 2022 Jun 13. doi:10.3389/fcvm.2022.927769 6. Minga I, Okwuosa T, Akhter N, et al. Developing a Model for Cross-Institutional Educational Collaborations. J Am Coll Cardiol CardioOnc. 2023 Apr, 5 (2) 262–266. 7. Power JR, Alexandre J, Choudhary A, et al. Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis [published correction appears in Circulation. 2021 Dec 7;144(23):e490]. Circulation. 2021;144(18):1521-1523. doi:10.1161/CIRCULATIONAHA.121.055816 Show Notes provided by: Abdelrahman Ali, MDCardio-Oncology FellowMD Anderson Cancer Center Department of Cardiology

Top 5 Most Read RNS's on Vox Markets for Thursday 23rd February 2023 5. Amigo Holdings #AMGO - 3rd Quarter Results Conversations with potential investors to underwrite a £45m equity raise continue. To date non-binding, indicative interest for between £10m to £15m of equity and £10m of exchangeable notes has been received. Revenue was £17.8M which down 76.5% from £75.7m 4. Ascent Resources #AST - Strategic Partnership, Equity Issue & TVR Ascent Resources announces the signature of a Strategic Collaboration Agreement with Beryl International Ltd, alongside agreeing a material equity investment by Beryl and the proposed appointment of a new Beryl nominated Non-Executive Director. In support of the collaboration, Beryl has agreed to subscribe for £1,000,000 in new equity via a direct subscription at 4p, being an 11% premium to the closing mid-market price of 3.6 pence on 22 February 2023. 3. Rolls-Royce Holdings RR. - 2022 Full Year Results - Underlying operating profit of £652m, £238m higher than the prior year, with the increase driven by Civil Aerospace and Power Systems - Free cash flow from continuing operations of £505m, £2.0bn higher than the prior year, led by engine flying hour recovery - Net debt of £3.3bn, down from £5.2bn at end 2021, due to disposals and improved cash flow 2. Helium One Global #HE1 - Company Update Helium One Global announces that the Company has entered into a co-operation agreement with Noble, pursuant to which Helium One and Noble have agreed to cooperate in sourcing and securing a suitable drilling rig, associated services and arranging logistics as required for the Company's proposed drilling campaign. 1. Avacta Group #AVCT - Avacta Therapeutics Division Science Day Avacta Group is today holding a Science Day, focused on its Therapeutics Division, for institutional investors and analysts as stated in the announcement on the 19 December 2022. The event will include a detailed review of the ongoing ALS-6000-101 Phase 1a clinical trial of AVA6000, Avacta's lead pre|CISION™ tumour targeted form of the chemotherapy drug Doxorubicin, in soft tissue sarcoma, as well as an update on preclinical programmes.

Drs Sumanta Pal and Mehmet Asim Bilen discuss the complexities of treating patients with non–clear cell renal carcinoma, the nuances of rare subtypes, and when to use chemotherapy vs immunotherapy. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/968741). The topics and discussions are planned, produced, and reviewed independently of advertiser. This podcast is intended only for US healthcare professionals. Resources Renal Cell Carcinoma https://emedicine.medscape.com/article/281340-overview Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology https://pubmed.ncbi.nlm.nih.gov/34991070/ PAPMET Trial: Testing Cabozantinib, Crizotinib, Savolitinib and Sunitinib in Kidney Cancer Which Has Progressed https://clinicaltrials.gov/ct2/show/NCT02761057 Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non–Clear-Cell Renal Cell Carcinoma and Genomic Correlates https://ascopubs.org/doi/10.1200/JCO.21.01944 Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605393/ Cabozantinib Plus Nivolumab Phase I Expansion Study in Patients With Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy https://aacrjournals.org/clincancerres/article/28/7/1353/682207/Cabozantinib-plus-Nivolumab-Phase-I-Expansion Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study https://ascopubs.org/doi/10.1200/JCO.21.00939 A Single-Arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients With Advanced Non–Clear Cell Renal Cell Carcinoma https://pubmed.ncbi.nlm.nih.gov/33867192/ ESMO 2022 https://www.esmo.org/meetings/esmo-immuno-oncology-congress-2022/abstracts Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma. The SAVOIR Phase 3 Randomized Clinical Trial https://jamanetwork.com/journals/jamaoncology/fullarticle/2766797 SAMETA: An Open-Label, Three-Arm, Multicenter, Phase III Study of Savolitinib + Durvalumab Versus Sunitinib and Durvalumab Monotherapy in Patients With MET-Driven, Unresectable, Locally Advanced/Metastatic Papillary Renal Cell Carcinoma (PRCC). https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.TPS4601 A Phase II Trial of Doxorubicin and Gemcitabine in Renal Cell Carcinoma With Sarcomatoid Features: ECOG 8802 https://pubmed.ncbi.nlm.nih.gov/21298497/ A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 9ER) https://clinicaltrials.gov/ct2/show/NCT03141177

This week, please join author Jonathan Sterne and Associate Editor Shinya Goto as they discuss the article "Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Oh, Greg, we've got a special treat for everyone today. We have a third co-host and he is none other than Peder Myhre from Norway! Really adding to the diversity of our podcast: me from Asia, you from the US, and Peder from Europe. Welcome, Peder. Dr. Peder Myhre: Thank you so much, Carolyn. It's truly an honor to be here and I'm looking forward to being part of this podcast today. Dr. Carolyn Lam: Awesome. Well, here we go. Looks like we have a feature paper, Greg? Dr. Greg Hundley: Absolutely, Carolyn. Peder, welcome. So, listeners, our feature today will involve COVID-19 and its association with arterial and venous thrombotic diseases. But before we get to that, we're going to all grab a cup of coffee from all over the world and get into some of the other articles in the issue. Peder, Carolyn, how about I go first? My first study involves a prospective cohort of 94,000 individuals from the UK Biobank, who had device-measured physical activity from 2013 to 2015 and were free from myocardial infarction and heart failure. Now, Peder and Carolyn, the study was performed because although objectively measured physical activity has been found associated with acute cardiovascular outcomes, it has not been found associated with heart failure and, of course, a syndrome that's been expanding worldwide. As such this study led by Carlos Celis-Morales from the University of Glasgow aimed to investigate the dose response relationship between device-measured physical activity and heart failure by intensity of the physical activity. Now physical activity was measured with a wrist-worn accelerometer and time spent on light, moderate, and vigorous intensity physical activity was extracted. Incidental heart failure was ascertained from linked hospital and death records. Dr. Peder Myhre: Wow, Greg. That sounds amazing. Tell us, what did they find? Dr. Greg Hundley: You bet, Peder! These investigators found that, compared with participants who undertook no moderate to vigorous intensity physical activity, those who performed 150 to 300 minutes per week of moderate intensity physical activity or 75 to 150 minutes per week of vigorous intensity physical activity were at lower risk of heart failure. Now, interestingly, the association between vigorous intensity physical activity and heart failure was a reverse J-shaped curve with a potentially lower risk reduction above 150 minutes per week. And so, the take-home message for this first paper is that device-measured physical activity, especially moderate intensity physical activity, was associated with a lower risk of heart failure. Probably current vigorous intensity physical activity recommendations should be encouraged, but not necessarily increased. In contrast, increasing moderate intensity physical activity may be beneficial, even among those meeting current recommendations. Dr. Peder Myhre: Wow, Greg. That was a great summary. And the second original research article today is about high density lipoproteins. As you know, raising HDL cholesterol levels to prevent cardiovascular disease remains a hot topic. HDL plays a key role in reverse cholesterol transport and may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin cholesterol acyl transferase, LCAT, is the rate limiting enzyme in the reverse cholesterol transport and a recombinant human LCAT called MEDI6012 has previously been shown to increase HDL cholesterol. So in this study from the corresponding author, Marc Bonaca from University of Colorado School of Medicine, the investigators in the real team is 63B multicenter placebo control trial investigated whether randomized patients to, MEDI6012 or placebo would reduce the infarct size as measured by cardiac MRI, 10 to 12 weeks after the STEMI. Dr. Greg Hundley: Very interesting, Peder. So, MRI assessments of LV mass after PCI. So, what did they find? Dr. Peder Myhre: So, Greg, the authors successfully enrolled 593 patients with a median age of 62 years and 78% males. And the median time from symptom onset to randomization was 146 minutes and only 13 minutes from hospitalization to randomization. And the index MI was anterior in 70% and 65% had TIMI Flow grade 0-1. And then to the main results at 12 weeks, the infarct size did not defer between the treatment group. So that was a 9.7% infarct size for MEDI6012 versus 10.5% for placebo with a P value of 0.79. And there was also no difference in noncalcified black volume. So the authors conclude that enhanced reverse cholesterol transport with recombinant human LCAT did not reduce infarct size or late regression of noncalcified coronary REPL at 12 weeks. Okay, Greg. So tell me about the 3rd paper you have today? Dr. Greg Hundley: Peder, what a great description on that previous paper, beautiful job there. So Peder, this next article pertains to cardio toxicity related to the administration of anthracycline-based chemotherapy. And an example would be Doxorubicin. And this occurs in patients often with certain types of cancer. As you know, Doxorubicin is still utilized for the treatment of leukemia, lymphoma, soft tissue sarcoma and in the setting of adjuvant breast cancer treatment. And so to this end, the authors, led by Lorrie Kirshenbaum from St. Boniface Hospital abstract research, wanted to assess cytokine mediated inflammation in myocellular injury, as a result of some of the inflammation that's induced by the administration of Doxorubicin. So as a little bit of background, cytokines, such as TNF alpha, have been implicated in cardiac dysfunction and toxicity associated with Doxorubicin. Now, while TNF alpha can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart really somewhat remain cryptic. The E3 ubiquitin ligase, TRAF2, provides a critical signaling platform for K63 length poly ubiquitin nation of rip K1, crucial for NF-kB activation by TNF alpha and survival. Whether alterations in TNF alpha, TRAF2, NF-kB activation signaling underlie the cardiotoxic effects of Doxorubicin, remains poorly understood. So herein, these authors investigated TRAF2 signaling in the pathogenesis of Doxorubicin cardio toxicity. Dr. Peder Myhre: Oh wow, Greg. So we're talking mitochondrial dysfunction in Doxorubicin cardiomyopathy. So please tell me, what did they find and what were the clinical implications? Dr. Greg Hundley: Very nice. Peder, you remind me of Carolyn, asking me the clinical implications. Okay, so first, in mouse models and in vitro measures in rats, mouse and human pluripotent stem cell derived cardiomyocytes, these investigators monitored TNF alpha levels, LDH, cardiac ultra structure and function, mitochondrial biogenics, as you just suggested, and cardiac cell viability. They found that a novel signaling axis exists that functionally connects the cardiotoxic effects of Doxorubicin to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by Doxorubicin, sensitizes cardiomyocytes to TNF alpha and BNIP3 mediated necrotic cell death. Perhaps, interventions that stabilize TRAF2, so here's the clinical implication, may prove beneficial in mitigating the cardiotoxic effects in cancer patients undergoing anthracycline-based chemotherapy. Dr. Carolyn Lam: So Greg, he may sound like me, but this is me going what an amazing summary and especially in something that is your specialty cardio-oncology, that's amazing. Thank you. Peder, I assume you've got one more paper? Dr. Peder Myhre: So Greg, now I'm going to sound like you and say that we are going to stay within the world of preclinical science. So genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease. However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. And there is evidence to suggest that the genetic influence of coronary artery disease sociability may partly act through vascular smooth muscle cells. So corresponding author, Shu Ye from University of Leicester, performed genotyping, RNA sequencing and cell behavior assays on the large bank of vascular smooth muscle cells with an N of almost 1500. And through these extensive analysis, they saw to identify genes whose expression was influenced by coronary artery disease associated variants. Dr. Greg Hundley: Very nice, Peder. So, more about cardiac gene expression. So, what did they find? Dr. Peder Myhre: Approximately 60% of the known coronary artery disease associated variants show statistically significant effects in vascular smooth muscle cells and the study identified 84 candidate causal genes whose expression quantitative trait, loci signals in vascular smooth muscle cells, significantly co-localized with reported coronary artery disease association signals, of which 38 of them are potentially druggable, so, that was the clinical implications. The authors conclude that a large percentage of coronary artery disease loci can modulate genes, gene expression in vascular smooth muscle cells and influence these cell behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. And Greg, accompanying this paper is a beautiful editorial by doctors O'Donnell and Bradner entitled "Bridging the Gap to Translating Genome-Wide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease." Dr. Greg Hundley: Very nicely done Peder, very nicely done. Well, as usual, we have some other items, we call it in the mail bag because we receive these wonderful research letters and also research correspondence. So I'll go first. First, Dr. Al-Khatib has a research letter entitled, "Duration of Anticoagulation Interruption before Invasive Procedures and Outcomes in Patients with Atrial Fibrillation Insights from the Aristotle Trial." And also there's a nice ECG analysis by Dr. Tsai entitled, "A Peculiar Wide-Complex Tachycardia During Flecainide Treatment." Dr. Peder Myhre: Nice, Greg, and there's also an exchange on letters to the editors and the response from Professors Zhao and Ding, and again, a response from Professor Zhang regarding the prior letter by Jin et al. pertaining to the previously published article "Micro RNA, 210 Controls, Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction." Dr. Greg Hundley: Beautifully done, Peder. Oh, wow. Welcome to this team. We're so excited to have you. And now Carolyn, I think we're going to jump over to that feature discussion and learn a little bit more about COVID-19 and arterial and venous thrombotic disease. Dr. Carolyn Lam: You bet! Let's go, Greg and Peder. Now we all know that infection with COVID 19 induces a pro-thrombotic state, but the long term effects of COVID-19 on the incidence of vascular disease, both arterial and venous, remain unclear. That is until today's feature paper. We're so grateful to have corresponding author Dr. Jonathan Stern, from the University of Bristol, as well as our associate editor, Dr. Shinya Goto from Tokai University School of Medicine to join us and discuss this very important paper today. Jonathan, could you start us off on telling us why it's so important to look at this? Haven't we always known that infections, COVID or not, are associated with pro-thrombotic state? So what's so different about what you did and what you found this time? Dr. Jonathan Stern: So, yes, I think we already knew that serious infections, in particular infections leading to hospitalization, can result in thrombotic events, either arterial or venous. And it was also clear from January, February, March 2020, that COVID led to very serious infection and therefore was likely to lead to vascular events. The questions that we set out to address, beyond simply establishing that COVID does indeed do this, was to quantify by how much COVID multiplies the rate at which these thrombotic events occurred, to do that separately for different events, such as myocardial infarction, stroke, venous thromboembolism, pulmonary embolism. And then to importantly, because we analyzed a very large dataset, which we might want to talk about, to try to separate out the amount by which the rating events was multiplied over time and in important subgroups, for example, in hospital people who were hospitalized for their COVID, compared with people who weren't hospitalized for their COVID, by age and sex, and by other demographic characteristics. Dr. Carolyn Lam: I love that, you see, that really set out the novel information this added with, may I add, very important clinical implications, which we'll get to them. You've already teed me up to talk about this 48 million adults that you managed to look at. Oh my goodness! Tell us, how in the world did you do that? Dr. Jonathan Stern: Well, I think the first thing to say is that it's my absolute privilege to talk about this paper on behalf of a really incredible team that put the work together. And a lot of that work, or that work started with really unlocking the power of NHS data because of the COVID pandemic. So in the UK, we have a national health service, free at the point of delivery to everybody. The NHS assembled electronic health records, and there's been a long and proud history of research based on electronic health records in the UK. But for the first time, because of the pandemic, a combined data resource for the whole of England, so that's a population of about 58 million people, was established and that linked primary care data - data from family doctors, data on secondary care hospital admissions, data on COVID testing and subsequently, although it's not the subject of this paper, data on vaccination. So those data were all linked and put into one place within what's called a trusted research environment with very strict controls on what can be output from the environment in order to protect patient privacy. And that was really done during 2020. And then the analyses for this paper took place during 2021, and it was an enormous amount of work by a large and absolutely fantastic team of people across multiple UK universities and national health service institutions. Dr. Carolyn Lam: Wow. Bravo! We talk about big data, we talk about using it. I trained in the NHS system. Who knew that this could come out to reveal such important results? So thank you for that as a background, but now, tell us what you found please? Dr. Jonathan Stern: So we found that rates of these conditions, they were primarily acute lymph infarction and ischemic stroke, which we grouped together with other conditions as arterial thrombotic events, and then deep vein thrombosis and pulmonary embolism, which we grouped together with other conditions as venous events. And we found that rates were substantially multiplied immediately after a diagnosis of COVID by up to 748 times, that the amount by which rates were multiplied diminished with time since COVID, but importantly that even six months to a year after that first diagnosis of COVID, rates of venous events were still about double in people who'd had COVID, compared to people who had COVID. And we found, it seemed quite clear that the persistence of the elevated risk was longer for venous events than for arterial events. Dr. Carolyn Lam: Just really fascinating results and Shinya, could I ask, what are your thoughts on this? And as you were managing this paper, the implications? Dr. Shinya Goto: First of all, thank you very much, Jonathan, for choosing saturation for your great paper. I'm handling quite a lot of papers, but your paper was very attractive. As Carolyn mentioned, it's huge data! 48 million, it's surprising, and also you also pick up booster rate of arterial embolism event for years, and you have also shown adjusted rate is initially increased quite a lot and then decreased gradually. And even after two months, three months still, there is a persisted higher risk. And as you mentioned, for the venous thrombo embolism, it's persisted for more than year to year. It's surprising. COVID-19's a different disease. Perhaps COVID-19 infection cuts to the vascular endarterial cell, perhaps, your research raised a lot of research questions, like endarterial damage induced by COVID-19 in the past 6 months; I would say more than half a year to one year. So that mechanistical insight is very important. And you raise a lot of any clinical questions. Dr. Jonathan Stern: Well, thank you very much for your kind words and you are right, I think we are left with questions about maybe in three areas. Firstly, for how long is there an elevation in risk? I should probably say, for those who haven't read the paper, that these results relate to events that occurred in England and Wales during 2020. And so that is in an era before vaccination and when we were dealing with the original variant, and to some extent, the alpha variant. So we are still waiting to see what the implications were over longer periods, and we will be doing that, we will be extending follow up. In fact, we are at the moment extending those results. I think, secondly, we are left with questions about the mechanisms, which you articulated, and thirdly, there's the question about, well, what are the implications for clinical management of patients with COVID-19? And in particular, for patients who've had severe COVID-19, for example, severe enough to be hospitalized for it? Dr. Shinya Goto: Yeah, you have also showed a very important point that even known hospitalization for COVID-19, the risk of thrombosis becomes high. So it's very surprising. And even non-hospitalized patients have a higher risk of thrombosis. That is probably the huge difference between other virus infections and COVID-19. Dr. Jonathan Stern: Yes. The good news, if you weren't hospitalized for your COVID, is that the elevation in risk declines more rapidly for people with less severe COVID who weren't hospitalized than for people with more severe COVID who were hospitalized. But nonetheless, as you say, particularly in the first week, two weeks, three weeks after COVID, there is a clear elevation in the risk of both arterial and venous events, even if you were not hospitalized for your COVID. We should probably also bear in mind that these results for 2020, when there were severe constraints for some of the time on health service resources. So you probably had to be pretty sick to get hospitalized at that time. Dr. Carolyn Lam: That was a very important caveat that you just highlighted. So thank you for contextualizing those findings for us, Jonathan, but then I kind of wish all podcast guests were like you, and you already asked a question, I was going to ask you. Which is, okay, so what's the clinical implication? Should we all be taking some low dose NOAC or aspirin? Whether you're hospitalized or not? Or if you were in 2020? Because, jokes aside, I know that you found some very important risk factors? Or these events which had clinical implications? Could you expand on it? Dr. Jonathan Stern: So maybe I'd start by saying that we didn't find that these patterns varied dramatically either by sex or by age. And in fact, when we were planning the analyses, I was convinced that we would see dramatic differences in these hazard ratios by age. And, broadly speaking, the facts on a multiplicative scale, the amount by which your rate is multiplied, looked similar across age groups and by sex. On the other hand, we did see the amount by rates of arterial and venous events were multiplied, appeared greater in people of Asian ethnicity or Black ethnicity than in people of White ethnicity. A counterintuitive finding was that the amount by which your rate was multiplied is lower, if you've had a prior event than if you hadn't. Those are the sorts of extents to which we can say something about how your own characteristics predict the consequences once you've had COVID. In terms of management, obviously the pandemic has been tumultuous for medicine and for medical research and things have moved on greatly since the pre-vaccination era, 2020 and early 2021, to which these analyses relate. So the first thing to say is, don't get hospitalized with COVID, and the best way to not be hospitalized with COVID, is to be fully vaccinated for COVID. And that's a message that I think the whole of the medical profession has communicated loudly and clearly for a long time now. So the second thing is, well, okay, what about if, nonetheless, you got COVID, particularly severe COVID, and we discussed this in the team extensively, and I particularly want to mention the senior clinical author, Dr. Will Whiteley from the University of Edinburgh in this regard, and I think the main message here is that risk factor management, cardiovascular risk factor management is always important, but it's probably particularly important in people who've had severe COVID to review risk factor management and make sure that existing guidelines in terms of cholesterol lowering, blood pressure lowering and so on, are being adhered to. We don't... So the most important thing is adherence to existing cardiovascular risk management guidelines. I think we don't have evidence that specific additional interventions are indicated in people who've had COVID, and COVID now in the era of Omicron and widespread vaccination is not the same as COVID during 2020. Dr. Shinya Goto: Jonathan, you have raised a very important issue. I strongly recommend all audiences to read this paper. We have to know persistent or higher risk of myocardial infarction, ischemic stroke, may be controlled more regularly controlled. Don't fear the COVID-19 infection to visiting the healthcare professional. In my country, some of the population stopped coming to the healthcare professional because they fear so much about infection from the hospital or clinic. But it's very important to keep that regular control like static and blood pressure control. Maybe we don't have that data about aspiring or not, but strong message your paper gave is that risk factor control after COVID-19 is very important. Dr. Jonathan Stern: I completely agree. Dr. Carolyn Lam: And I would add to that, remember the days when people were stopping their ACE inhibitors and so on for those fear? So what a great message and thank you for giving us a little bit of a peek into the future of what you're planning next with more follow up, in a population that is vaccinated from a different strain perhaps. And I think this still encourages hopefully more trials and research into this whole area of how we should be managing these patients. Well, thank you so much both of you for discussing this very, very current relevant, important paper. Thank you for publishing it in circulation with us. And to the audience, thank you for joining us today. From Greg and I, you've been listening to Circulation on the Run, and don't forget to tune in again next week. Speaker 6: 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 or of the American Heart Association. For more, please visit ahajournals.org.

This recording features audio versions of July 2022  Journal of Vascular and Interventional Radiology (JVIR) abstracts:Polyethylene Glycol Drug-Eluting Embolic Microspheres Loaded with Doxorubicin for the Treatment of Hepatocellular Carcinoma: Feasibility, Safety, and Pharmacokinetic Study, Malagari, et al.  READ Impact of Chemoembolic Regimen on Immune Cell Recruitment and Immune Checkpoint Marker Expression following Transcatheter Arterial Chemoembolization in a VX2 Rabbit Liver Tumor Model, Berz et al. READRadiation Segmentectomy for the Treatment of Solitary Hepatocellular Carcinoma: Outcomes Compared with Those of Surgical Resection, De la Garza-Ramos et al. READRadioembolization for Hepatocellular Carcinoma: The Effects of Arterioportal Shunts on Nontargeted Liver Hypertrophy, Park et al. READSafety and Efficacy of Percutaneous Cryoablation of Extraspinal Thyroid Cancer Bone Metastases with Curative Intent: Single-Center Experience with a Median Follow-up of More than 5 Years, Autrusseau et al. READOutcomes of Irreversible Electroporation for Perihilar Cholangiocarcinoma: A Prospective Pilot Study, Franken et al. READMR Imaging Biomarkers for the Prediction of Outcome after Radiofrequency Ablation of Hepatocellular Carcinoma: Qualitative and Quantitative Assessments of the Liver Imaging Reporting and Data System and Radiomic Features, Petukhova-Greenstein et al. READIndependent Predictors of Major Adverse Cardiovascular Events at 3 Years After Aortoiliac stent implantation, Yamauchi et al. READComparing Endovascular and Surgical Treatments for Varicocele: A Systematic Review and Meta-Analysis, Liu et al. READMaskless 2-Dimensional Digital Subtraction Angiography Generation Model for Abdominal Vasculature using Deep Learning, Yonezawa et al. READJVIR and SIR thank all those who helped record this episode:Host:Sanna Herwald, MD, PhDAbstract readers:Alex Ghorishi, Florida Atlantic University, Charles E Schmidt College of MedicineJonah Sens, Georgetown University School of MedicineTalal Mourad, University of Illinois at PeoriaPriya Gupta, Rutgers New Jersey Medical SchoolDerek Yuan, Touro University College of Osteopathic Medicine in CaliforniaVanessa Lisseus-Wright, American University of AntiguaRichard Liang, New York Institute of Technology College of Osteopathic MedicineD'Shaun Adams, University of Central FloridaEric Cooper, University of Illinois at ChicagoTy Mattinson, University of Washington School of Medicine Audio editor:Eshani Choksi, Rowan University School of Osteopathic Medicine©  Society of Interventional RadiologySupport the show

Dr. Stephen Ansell, of the Mayo Clinic in Minnesota, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about ECHELON-1's compelling overall survival analysis in newly diagnosed Hodgkin lymphoma and key advances in the SHINE, MOMENTUM, and ASCEMBL trials that were featured at the 2022 ASCO Annual Meeting.   TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast.  My guest today is Dr. Stephen Ansell, a professor and chair of medicine at the Department of Hematology at the Mayo Clinic in Minnesota. Dr. Ansell shares his insights on key advances in hematologic malignancies that were featured at the 2022 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on podcasts can be found on our transcripts at asco.org/podcasts.   Stephen, it's great to have you on the podcast today.  Dr. Stephen Ansell: Thanks so much for having me, John.  Dr. John Sweetenham: So, Stephen, I'd like to start with your thoughts on Abstract 7503, which of course is one that you authored, and this is a 6-year follow-up study of the ECHELON-1 trial. This includes a positive overall survival analysis for brentuximab vedotin in newly diagnosed advanced Hodgkin lymphoma. Can you tell us more about this?  Dr. Stephen Ansell: Yeah, sure, John. And you know, as you point out, the thing that's really interesting and unique about this trial is we haven't had a lot of studies in Hodgkin lymphoma that show an overall survival advantage as you well know. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy has actually been quite difficult to beat when it's been an overall survival endpoint that one has been looking at.  There have been some other strategies in the past that have been looked at—the escalation of therapies such as escalator BEACOPP, and maybe modification of therapy to minimize toxicity, such as the RATHL trial where bleomycin is dropped out.  In all of these studies, there have been advantages for progression-free survival, but not clearly against ABVD as the standard and overall survival advantage. So, our listeners would probably know that ECHELON-1 was a comparison between brentuximab vedotin ABVD chemotherapy, and ABVD chemotherapy as the standard, showing an initially modified progression-free survival advantage and subsequently a progression-free survival advantage. But now with 6 years of follow-up, an overall survival advantage. And I think that's really what makes this quite unique.  Dr. John Sweetenham: One of the reasons I think many people, myself included, thought that it was going to be a very high bar to show an overall survival difference in this study was simply the fact that treatments to relapsed and refractory Hodgkin lymphoma, in general, have improved really quite substantially, both before and during the conduct of this trial.  Do you have any thoughts on that? Were you surprised? And any thoughts on why we're seeing this in the face of the rapidly evolving treatment landscape in the relapse setting?  Dr. Stephen Ansell: Yeah, I think that's an excellent point. And, John, I think there have been 2 schools of thought, as you know, those that have felt that the first shot was always the best one. And you should go hard right off the bat and others have said, you don't need to give everybody intensive treatment, because as you say, subsequent therapies can be very effective.  This would actually challenge that second position because when we looked at how patients were managed in both groups when they relapsed, the vast majority of relapsing patients in the group that got ABVD subsequently got brentuximab vedotin, as part of their regimen. Most patients—and it was balanced in both arms—got the standard kind of salvage treatment, autologous stem cell transplant approach, and some patients in both arms, got novel agents, including PD1 blockade, that was a minority, partly because of the timing of when the study was done.  But I think all of the things that we would normally do were done, and yet there's still a survival advantage. The one interesting thing I think that's worth taking away from this is when one looked at some of the influences on what might have made that overall survival difference, there were more patients progressing and dying from Hodgkin's in the ABVD arm suggesting that adding brentuximab vedotin does make a difference to the disease itself. But also interestingly, there were fewer patients in the brentuximab arm, who got a second lymphoma.  And interestingly, there were quite a substantial number of people in the ABVD arm when they relapsed to or subsequently got a different lymphoma, suggesting that the brentuximab vedotin, may actually target a precursor cell in a heme malignancies space and actually may have a benefit that way.  Dr. John Sweetenham: So, what's your overall conclusion from this study now that brentuximab vedotin plus ABVD is the standard of care for patients with newly diagnosed advanced Hodgkin lymphoma?  Dr. Stephen Ansell: I would say that if you have advanced-stage disease with classical Hodgkin lymphoma histology, it's very difficult not to say that this would be the standard of care to manage the patients.  I think we've learned that this study applied to older patients who are often difficult to treat. And so, hence, that's also a very valid treatment to give. And it's very difficult to argue against giving treatment that has an overall survival advantage for patients. So, in my practice, this has become the standard of care.  Dr. John Sweetenham: Okay, great. Thanks, Stephen. Let's move on and talk about LBA7502. This reported on the primary results of a double-blind placebo-controlled study known as SHINE, which looks at the use of ibrutinib in combination with bendamustine and rituximab followed by rituximab maintenance as a first-line treatment for older patients with mantle cell lymphoma. What are your thoughts and key takeaways from this study?  Dr. Stephen Ansell: Again, I think this is a very important study in older patients with mantle cell lymphoma. So, as you well know and many of our listening audience would know that we kind of has 2 strategies in mantle cell lymphoma. In younger patients, we may treat them with a more intense approach, sometimes with autologous stem cell transplant, often with a kind of alternating high-intensity therapies.  For patients who are older, bendamustine rituximab is really a standard therapy for patients with that demographic. And this now really pushes the field forward by showing that if you take bendamustine rituximab and add ibrutinib an effective therapy in the relapse setting, in the upfront setting, there is a substantial advantage for how patients do.  If one looks at the overall outcomes, it shows that progression-free survival is improved; we don't have overall survival benefit yet. But as we track these patients, it'll be interesting to see if that does transpire in time.  I will say again that I always like placebo-controlled arms because it helps us really get a handle on toxicities. And in general, in this population of patients, it was well tolerated. So, I think this, again, is a regimen that is going to be very useful in older patients.  Dr. John Sweetenham: I think that the lack of an overall survival benefit so far could of course be because there was a crossover in a study for those patients who progressed on the placebo-controlled arm.  But my other question about this, just to get your impression, is that there is a subgroup of elderly patients or older patients with a very slowly progressive disease where the management approach has been more of a watch-and-wait and observation-only approach until they become symptomatic. Do you think results like this, which start to show a progression-free survival benefit from upfront therapy, change that philosophy? Should we be thinking harder about whether anyone should be observed now?  Dr. Stephen Ansell: I think that's a good question. And to be frank, I will say that in my practice, I still have a spirit of, I'm happy to watch patients who have a very low burden of disease to just get a sense of the pace of the disease. Because as you say, you may be surprised by a subset of patients whom you may not need to treat for a year or even longer. And my view is that a year of no treatment is always better than a prolonged progression-free survival interval on treatment. So, I take the view that if you don't need to treat, that is still the best management.  Dr. John Sweetenham: Great, thank you! So, we're going to change gear for a moment and move out of lymphoid malignancy and talk a little about Myeloproliferative Syndrome. I'm interested to hear your thoughts on the MOMENTUM study. So, this was Abstract 7002, another phase 3 randomized study, in this case, looking at the use of momelotinib versus danazol in symptomatic and anemic patients with Myelofibrosis, who previously had a JAK inhibitor. What are your thoughts on this study?  Dr. Stephen Ansell: I think again, this is really good and very interesting data because those that treat Myelofibrosis will know these are challenging to treat. And many times, the symptoms they experience, the transfusion challenges they have, and the difficulty they have with very large spleens are all things that impact the quality of life quite profoundly. And therapies, in general, that would benefit those symptoms are always highly valuable.  So, I did find, again, I'm not as much of an expert in Myelofibrosis, but certainly, my colleagues who are were very satisfied with these results, basically showing improvement when compared to danazol, which again, I would anticipate as modest control with not particularly good efficacy, again, some of those symptoms I just spoke about, but momelotinib really showed a substantial benefit for the symptoms that this disease causes, and obviously transfusion requirements and improved spleen sizes and spleen symptoms.  So, I think in general, for managing patients for whom the quality of life is profoundly impacted, this is going to be a useful agent moving forward.  Dr. John Sweetenham: Okay, great. Thanks. And staying on the theme of Myeloid diseases, Abstract 7004 reported on the efficacy and safety, from the so-called ASCEMBL study, another phase 3 study, in this case, looking at the use of asciminib versus bosutinib in patients with Chronic Myeloid Leukemia (CML) who are in chronic phase, and who had already received 2 or more tyrosine kinase inhibitors. And this was an update at week 56 of the study. Why do you think this study should be on our radar?  Dr. Stephen Ansell: Well, I think again, we're always looking for agents that make a difference, particularly with subsequent lines of therapy in this disease. I think bosutinib is really regarded as a standard of care in this population of patients and an agent that comes along, ascitinib in this case, that shows a significant benefit, that really brings yet another tool for us to utilize in these patients.  I must say, again, as I looked at the results, comparing also looking for the major molecular responses, and the benefit and durability thereof, this was pretty impressive data. And so, I think it's very useful in this disease to have a plethora of tools that we can reach to be able to really impact the outcome of patients. So, I think, again, this is highly relevant data that we would use in the clinic in the not-distant future.  Dr. John Sweetenham: Do you think it's likely it'll move into frontline treatment over time?  Dr. Stephen Ansell: So, I think that is a good question. I don't know the answer to that, except to say that these results are pretty impressive. And so, I do believe that that's going to need to be tested, but as has been done in CML over the decades and which is really to be applauded, there have been randomized trials, comparing head-to-head agents showing which agent really has the greatest benefit and efficacy. So, I'll watch that space with a lot of interest.  Dr. John Sweetenham: Thanks! And finally, I'd like to return to lymphoid malignancy. In the 2020s, it would be almost impossible to review a meeting such as ASCO without saying something about CAR T-cell therapy, and this podcast is going to be no exception.  So, I wonder if I could get your thoughts on Abstract 7571. And this was an abstract, which reported real-world outcomes for axicabtagene ciloleucel, otherwise known as the Axi-Cel, for the treatment of large B-cell lymphoma. And it looked at the outcomes according to race and ethnicity. What are your thoughts on this study?  Dr. Stephen Ansell: Well, John, I smiled when you were said there's not a possible to really have a conversation without bringing in CAR T-cell somewhere along the way, but what I liked about this abstract, is it really was bringing in the real-world data, because many times and again, I have to stress that real-world data, when it comes to CAR T-cells is probably not the real world in the most real-world nature of things. And that is just you have to have access to certain centers to be able to get this therapy. And I think that's what this abstract actually points to.  It does look at almost 1,400 patients treated with Axi-Cel. And now that in large cell lymphoma, this is a standard of care where we either use a post-transplant and now even as a first relapse therapy, this is becoming highly relevant. And the question is just always seeing discrepancies between various population groups when we look at how outcomes transpire from this therapy.  And as it turns out, if one looks at Asian populations, those are really not adversely impacted, or Hispanic populations. But the African American population continues to have a less favorable outcome, even with this sophisticated therapy.  And that does suggest that possibly, when those patients, in general, can get access to this care, might actually be a little later in the disease, greater disease burden, possibly a little later line of therapy, resulting in not as favorable results.  I think this is whereas health care providers, we need to turn our attention in the future. And that is to say, how can we make care be equally good for all patients everywhere within our country, rather than there being nuggets where certain people benefit a lot and other areas where people benefit very little.  Dr. John Sweetenham: Yeah, thank you. There was good discussion after this study was presented and I think much of it focused around exactly what you've just said. Most of this difference is almost certainly not biological but it's really related to access to care and so on and that was an important take-home message. So, thanks for emphasizing that.  Stephen, thanks so much for sharing your insights with us today regarding the 2022 ASCO Annual Meeting on our podcast. I really appreciate your being willing to talk to us.  Dr. Stephen Ansell: John, thank you very much for having me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Stephen Ansell:  Honoraria: WebMD, Research to Practice  Research Funding (Inst.): Bristol-Myers Squibb, Seattle Genetics, Affimed Therapeutics, Regeneron, Trillium Therapeutics, AI Therapeutics, ADC Therapeutics  Disclaimer:  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, 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.       

On this week's SciFiles, your hosts Chelsie and Daniel interview Zach Miller. A therapeutic window is a dose range between the minimum effective drug dose (MED) to the minimum toxic drug dose (MTD). Many commonly-used cancer drugs, including chemotherapies such as Doxorubicin, are highly toxic to normal tissues and have narrow therapeutic windows. The drug concentration should constantly remain between the MED and MTD in order to produce risk-free therapeutic effects. In general, critically, administration of too much drug (above the therapeutic window) will cause serious side effects on normal human organs, leading to patient morbidity or even death. On the other hand, too little drug (below the therapeutic window) will result in a lack of treatment efficacy and may induce cancer drug resistance, which is the most important reason for the failure of chemotherapy. Herein, we studied the viability of two cell lines, a dox-sensitive cell line (BT459) and a non-dox-sensitive cell line (4T1), to estimate the therapeutic window of doxorubicin. We studied the cell viability to estimate the therapeutic window of DOX in vitro so as to guide the DOX dose in vivo.If you're interested in talking about your MSU research on the radio or nominating a student, please email Chelsie and Danny at scifiles89fm@gmail.com. Check The Sci-Files out on Twitter, Facebook, Instagram, LinkedIn, and YouTube! 

Lauren and JJ investigate a case of collapse in a middle-aged dog. This episode includes a detailed discussion of hemoabdomen and splenic hemangiosarcoma in the dog. References Primary sources of information for this episode: (1) Rothrock, K., Smrkovski, K., & Rosenthal, R. C. (2021). Hemangiosarcoma, splenic (canine). VINcyclopedia. Last updated 5/8/2021. Last accessed 5/26/2022. www.vin.com (2) Pope, K. (2018). Evidince-informed integrative oncology: Canine splenic hemangiosarcoma. Southwest Veterinary Symposium Proceedings, 2018. Information about rates of metastasis, splenectomy as a palliative procedure, and poor overall survival rates: (1) Pope, K. (2018). Evidince-informed integrative oncology: Canine splenic hemangiosarcoma. Southwest Veterinary Symposium Proceedings, 2018. (2) Clifford, C. A. & Liptak, J. M. (2017). Splenic tumors. Atlantic Coast Veterinary Conference Proceedings, 2017. (3) Batschinski, K., Nobre, A., Vargas-Mendez, E., Tedardi, M. V., Cirillo, J., Castari, G., Ubukata, R., & Dagli, M. L. (2018). Canine visceral hemangiosarcoma treated with surgery alone or surgery and doxorubicin: 37 cases (2005-2014). The Canadian Veterinary Journal, 59(9), 967-972. (4) Wendelburg, K. M., Price, L. L., Burgess, K. E., Lyons, J. A., Lew, F. H., & Berg, J. (2015). Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001-2012). Journal of the American Veterinary Medical Association, 247(4), 393-403. Information about median survival times: (1) Thamm, D., Withrow, S. W. (2013). Miscellaneous tumors: Hemangiosarcoma. Withrow & MacEwen's Small Animal Clinical Oncology,St. Louis, MO. Saunders/Elsevier, 679-88. (2) Aronsohn, M. G., Dubiel, B., Roberts, B., & Powers, B. E. (2009). Prognosis for acute nontraumatic hemoperitoneum in the dog: a retrospective analysis of 60 cases (2003-2006). Journal of the American Animal Hospital Association, 45(2), 72–77. (3) Collard, F., Nadeau, M. E., & Carmel, E. N. (2010). Laparoscopic splenectomy for treatment of splenic hemangiosarcoma in a dog. Veterinary surgery : VS, 39(7), 870–872. (4) Marconato, L., Chalfon, C., Finotello, R., Polton, G., Vasconi, M. E., Annoni, M., Stefanello, D., Mesto, P., Capitani, O., Agnoli, C., Amati, M., & Sabattini, S. (2019). Adjuvant anthracycline-based vs metronomic chemotherapy vs no medical treatment for dogs with metastatic splenic hemangiosarcoma: A multi-institutional retrospective study of the Italian Society of Veterinary Oncology. Veterinary and comparative oncology, 17(4), 537–544. A selection of information about chemotherapy and adjunctive treatments for hemangiosarcoma (outside of the scope of this episode, for further reading): (1) Wendelburg, K. M., Price, L. L., Burgess, K. E., Lyons, J. A., Lew, F. H., & Berg, J. (2015). Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001-2012). Journal of the American Veterinary Medical Association, 247(4), 393-403. (2) Alexander, C. K., Cronin, K. L., Silver, M., Gardner, H. L., & London, C. (2019). The addition of metronomic chemotherapy does not improve outcome for canine splenic haemangiosarcoma. Journal of Small Animal Practice, 66(1), 32-37. (3) Matsuyama, A., Poirier, V. J., Mantovani, F., Foster, R. A., & Mutsaers, A. J. (2017). Adjuvant doxorubicin with or without metronomic cyclophosphamide for canine splenic hemangiosarcoma. Journal of the American Animal Hospital Association, 53(6), 304-312. (4) Teske, E., Rutteman, G. R., Kirpenstein, J., & Hirschberger, J. (2011). A randomized controlled study into the efficacy and toxicity of pegylated liposome encapsulated doxorubicin as an adjuvant therapy in dogs with splenic haemangiosarcoma. Veterinary and Comparative Oncology, 9(4), 283-89. (5) Kahn, S. A., Mullin, C. M., de Lormier, L. P., Burgess, K. E., Risbon, R. E., Fred, R. M., Drobatz, K., & Clifford, C. A. (2013) Doxorubicin and deracoxib adjuvant therapy for canine splenic hemangiosarcoma: A pilot study. The Canadian Veterinary Journal, 54(3) 237-42. (6) Kim, S. E., Liptak, L. M., Gall, T. T., Montelth, G. J., & Woods, P. (2007). Epirubicin in the adjuvant treatment of splenic hemangiosarcoma in dogs: 59 cases (1997-2004). Journal of the American Veterinary Medical Association, 231(10), 1550-57. (7) Alvarez, F. J., Hosoya, K., Lara-Garcia, A., Kisseberth, W., & Couto, G. (2013). VAC protocol for treatment of dogs with stage III hemangiosarcoma. Journal of the American Animal Hospital Association, 49(6), 370-77. (8) Marconato, L., Chalfon, C., Finotello, R., Polton, G., Vasconi, M. E., Annoni, M., Stefanello, D., Mesto, P., Capitani, O., Agnoli, C., Amati, M., & Sabattini, S. (2019). Adjuvant anthracycline-based vs metronomic chemotherapy vs no medical treatment for dogs with metastatic splenic hemangiosarcoma: A multi-institutional retrospective study of the Italian Society of Veterinary Oncology. Veterinary and Comparative Oncology, 17(4), 537-44. (9) Gardner, H. L., London, C. A., Portela, R. A., Nguyen, S., Rosenberg, M. P., Klein, M. K., Clifford, C., Thamm, D. H., Vail, D. M., Bergman, P., Crawford-Jakubiak, M., Henry, C., Locke, J., & Garrett, L. D. (2015). Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma. BioMed Central Veterinary Research, 11(0), 131. (10) Lana, S., U'ren, L., Plaza, S., Elmslie, R., Gustafson, D., Morley, P., & Dow, S. (2007). Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. Journal of Veterinary Internal Medicine, 21(4), 764-69. (11) Vail, D. M., MacEwen, E. G., Kurzman, I. D., Dubielzig, R. R., Helfand, S. C., Kisseberth, W. C., London, C. A., Obradovich, J. E., Madewell, B. R., & Rodriguez, C. O. (1995). Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine adjuvant immunotherapy for splenic hemangiosarcoma in the dog: a randomized multi-institutional clinical trial. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 1(10), 1165-70. (12) Grammel, T. (2016). A pilot, uncontrolled study of postsurgical treatment with autologous dendritic cell-based immunologic therapy in 10 dogs with splenic hemangiosarcoma. Veterinary Cancer Society World Congress Proceedings, 2016.

In this episode from the series “Key Decisions in HIV Care,” Cristina Mussini, MD, and William R. Short, MD, MPH, AAHIVS, discuss important considerations for ART with opportunistic infections, including: When to start ART with pneumocystis pneumonia including discussion of the ACTG 5164 study of immediate vs delayed ART with opportunistic infectionsEACS, DHHS, and IAS-USA guideline recommendations for starting ART in the setting of most opportunistic infectionsConsiderations for the administration of ART to patients who are unable to swallow or critically ill and intubatedTreatment of Kaposi sarcoma and considerations for starting ART to avoid drug–drug interactions with Kaposi sarcoma treatmentConsiderations for starting ART with cytomegalovirus and the risk for IRIS from cytomegalovirusDiscussion of treatment of cytomegalovirus and overlapping toxicities between its treatment and ARTWhen to start ART with cryptococcal meningitis and the data to support delayed treatment initiation with this particular opportunistic infectionEACS, DHHS, and IAS-USA guideline recommendations for starting ART in the setting of cryptococcal meningitis specificallyTreatment of cryptococcal meningitis and managing drug–drug interactions between ART and antifungal therapyPresenters:Cristina Mussini, MDHead of Department of Infectious Diseases and Tropical MedicineFull Professor of Infectious DiseasesInfectious Diseases Clinics University HospitalUniversity of Modena and Reggio EmiliaReggio Emilia, Italy William R. Short, MD, MPH, AAHIVSAssociate Professor of MedicineDivision of Infectious DiseasesDepartment of MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphia, Pennsylvania Content based on an online CME program supported by educational grants from Gilead Sciences, Inc.; Janssen Therapeutics, Division of Janssen Products, LP; and ViiV Healthcare.Follow along with the slides at:https://bit.ly/3uktrm1Link to full program:https://bit.ly/3q2DlGd

We return to our Landmarks of OncoPharm series to dive deep into an article that provided some of our foundational understanding of how anthracycline cardiotoxicity risk is influenced by rate of administration. Link: https://pubmed.ncbi.nlm.nih.gov/2910423/

Commentary by Dr. Nathan Wang

Most people are aware by now that exercise has positive effects in “healthy” individuals and in patients with cancer. In cancer patients, exercise has been shown to reduce adverse events, improve quality-of-life and respiratory fitness, and even decrease the risk of breast cancer recurrence. These results, and many others, have prompted major national and international cancer organizations to make exercise recommendations. “There also is a growing body of evidence that exercise may directly alter the tumor microenvironment to influence tumor growth, metastasis, and response to anticancer therapies.” However, scientists and researchers have only scratched the surface of understanding the extent of the benefits that are capable of being harnessed by exercise. While research shows that exercise may impact tumors, the exercise prescription needed to induce these beneficial tumor-related outcomes is still unclear. In an effort to better harness the benefits of exercise, researchers from the University of Florida conducted a study on the effects of wheel running in breast cancer mouse models and chemotherapy. Their paper was published as the cover of Oncotarget's Volume 12, Issue 18, and entitled, “Normal tissue and tumor microenvironment adaptations to aerobic exercise enhance doxorubicin anti-tumor efficacy and ameliorate its cardiotoxicity in retired breeder mice.” “The goal of this study was to characterize the exercise prescription by evaluating the aerobic adaptations in both the normal tissue and the tumor microenvironment. Moreover, doxorubicin was used to assess the adjuvant effects of aerobic exercise on chemotherapy efficacy and toxicity.” Full blog - https://www.impactjournals.com/journals/blog/oncotarget/new-study-how-exercise-boosted-chemotherapy-in-mice/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28057 DOI - https://doi.org/10.18632/oncotarget.28057 Full text - https://www.oncotarget.com/article/28057/text/ Correspondence to - Zachary R. Wakefield - zwakefield@ufl.edu Keywords - aerobic exercise, breast cancer, hypoxia, doxorubicin, cardiotoxicity About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

This episode covers doxorubicin and daunorubicin!

Commentary by Dr. Virginia Hahn

HOPA Now is the official podcast of the Hematology/Oncology/Pharmacy Association, an organization dedicated to supporting pharmacy practitioners and promoting the advancement of Hematology/Oncology/Pharmacy to optimize the care of individuals impacted by cancer.   These educational podcasts are part of our BCOP Preparatory and Recertification Course, which is designed to prepare oncology pharmacists preparing to sit for the BCOP Certification Exam, as well as meet the BPS requirement to complete a BCOP Preparatory/Recertification Review Course.   In this episode of HOPA Now, Dr. Christy Harris addresses the top ten clinical pearls regarding adult sarcomas, including an overview of the approval, dosage, and warnings of various drug treatments including doxorubicin, avipritinib, pexidartinib, and tazemetostat. She concludes with recommendations for regimens and collaborations that will produce optimal results for all clinical trials and patients.   In this episode, you will learn:   Adult Sarcomas: Top 10 Clinical Pearls An overview of the origin and main categories of sarcoma cancers Doxorubicin as the standard treatment option for sarcoma cancers Recommendations for dosage and monitoring of ifosfamide-induced encephalopathy Targets as an area of possible therapeutic benefit in various sarcomas An overview of the newly recognized gastrointestinal stromal tumor (GIST) The role, approval, and warnings associated with the new drugs avipritinib and pexidartinib Understanding epithelioid sarcomas next new therapy — tazemetostat Oral targeted therapies that best demonstrate advancement in the cancer arena   Mentioned in This Episode: HOPA   Quotes:   “Sarcomas are a large, heterogeneous group of cancers that arise from connective tissues such as bone, skeletal and smooth muscle, adipose tissue and cartilage.” — Dr. Christy Harris   “Doxorubicin remains the standard for treatment for most sarcomas. Other agents may be added to it, but doxorubicin remains the workhorse of the sarcoma world.” — Dr. Christy Harris   “Targets have been identified as possible areas of therapeutic benefit for a number of sarcomas.” — Dr. Christy Harris   “Sarcomas are an uncommon tumor for most clinicians to see, but there is an increasing number of oral targeted therapies for individual tumors that demonstrate some advancement in the cancer arena.” — Dr. Christy Harris  

Commentary by Dr. Paul Burridge

This month on Episode 15 of the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from the July 31 and August 14 issues of Circulation Research. This episode features an in-depth conversation with Drs Venu Venna and Juneyoung Lee from the Department of Neurology at the McGovern Medical School at the University of Texas Health Science Center at Houston regarding their study Gut Microbiota-Derived Short-Chain Fatty Acids Promote Post-Stroke Recovery in Aged Mice. This episode also includes a brief discussion with BCVS Outstanding Early Career Investigator Award competition finalists, Drs Shyam Bansal from Ohio State University, Emmanouil Tampakakis from Johns Hopkins University, and Yang Zhou from the University of Alabama, Birmingham.   Article highlights:   Veys, et al. GLUT1 in Angiogenesis and BBB Integrity   Zhang, et al. Self-Renewal of Local Macrophages Attenuates DiCM   Lerchenmüller, et al.  CITED4 in Cardiac Remodeling     Dr Cindy St. Hilaire:        Hi. Welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh. Today I'm going to share with you three articles selected from the late July and early August issues of Circulation Research. I'm also excited to share with you my discussions with Drs Venugopal Venna and Juneyoung Lee, who are from the group of Louise McCullough at the University of Texas Health Science Center, regarding their study Gut Microbiota-Derived Short-Chain Fatty Acids Promote Post-Stroke Recovery in Aged Mice. I also speak with the finalists of the BCVS Outstanding Early Career Investigator Award, Shyam Bansal from Ohio State University, Emmanouil Tampakakis from Johns Hopkins University, and Yang Zhou from the University of Alabama, Birmingham. So first the highlights. The first article I'm sharing with you is titled Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity. The first author is Koen Veys and the corresponding author is Katrin De Bock from ETH Zurich. The primary energy source for the brain is glucose and the blood vessel endothelial cells which from the blood-brain barrier supplied glucose to the brain via the glucose transporter protein GLUT1. Patients with genetic mutations in GLUT1 have neurological problems, including seizures, movement disorders, and delayed neurological development. Low GLUT1 levels in the blood-brain barrier have also been linked to Alzheimer's disease in humans and have been known to exacerbate the disease in a mouse model. In this study, the group examined the role of GLUT1 in blood-brain barrier endothelial cells in more detail. They found that while structural integrity of the blood-brain barrier remained intact, inhibiting the activity of GLUT1 in newborn mice impaired aspects of normal blood vessel growth in the brain, and inhibiting GLUT1 in adult mice led to progressive neuron loss, behavioral abnormalities, reduced movement, seizures, and signs of inflammation. The results highlight GLUT1's importance in the brain endothelial cells, and the role of GLUT1 in glucose utilization in overall brain function. The second article I want to share with you is titled Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-induced Cardiomyopathy Through the SR-A1-c-Myc Axis. The first authors are Hanwen Zhang, Andi Xu, Xuan Sun, and the corresponding author is Qi Chen and the work was completed at Nanjing Medical University in China. Doxorubicin and it's analogues are commonly used chemotherapeutic agents. However, the use of these drugs is limited by dose-dependent cardiotoxicity. Doxorubicin-induced cardiomyopathy presents with dilated and poorly functioning left ventricle in the absence of abnormal loading conditions. This may induce cardiac systolic dysfunction. Accumulating clinical evidence suggests that inflammation contributes to doxorubicin-induced cardiomyopathy pathogenesis. Several studies suggest that the inhibition of cardiac inflammation can improve cardiac function; however, the underlying mechanisms remain unclear. This group wanted to explore the role of cardiac resident macrophages during doxorubicin-induced cardiomyopathy progression. They found that cardiac resident macrophages were vulnerable to doxorubicin insult but that monocyte-derived macrophages survived. Further, these surviving monocyte-derived macrophages exhibited a proinflammatory phenotype which contributed to impaired cardiac function. Scavenger receptors are expressed on macrophages and help to modulate their inflammatory response. Global, or myeloid-specific deletion of class A1 scavenger receptor, also called SR-A1, inhibited proliferation of resident reparative macrophages and this inhibition exacerbated cardiomyopathy. At the mechanistic level, this group identified that the transcription factor c-Myc mediated the effect of SR-A1 in reparative macrophage proliferation in doxorubicin-induced cardiomyopathy. The last article I want to share with you before we switch to our interviews is titled CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress. The first author is Carolin Lerchenmüller and the corresponding author is Anthony Rosenzweig, and they're from Massachusetts General Hospital. Exercise is good for the heart. It increases cardiac mass which is called physiological hypertrophy, which appears to induce cardiac benefits. However, pathological stimuli, such as hypertension and aortic stenosis, can lead to pathological hypertrophy which is associated with adverse outcomes and can lead to heart failure. Cardiac CITED4 is a protein that is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown. To understand the role of endogenous cardiomyocyte CITED4, this groups generated cardiomyocyte specific knockouts of CITED4. These mice were analyzed at baseline. They were subjected to a swimming protocol which provided physiological stimuli or they underwent transverse aortic constriction, also called TAC, which causes pressure overload and served as the pathological stimulus for heart remodeling. CITED4 knockout mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, these knockouts developed severe heart failure with left ventricular dilation and impaired cardiomyocyte growth. The study goes on to show that CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and also a network of microRNAs which control cardiomyocyte to fibroblast crosstalk. So for our interview of this episode, I have with me Drs Venugopal Venna and Juneyoung Lee from the Department of Neurology at the McGovern Medical School at the University of Texas Health Science Center at Houston. Today we're going to be discussing their manuscript titled Gut Microbiota-Derived Short-Chain Fatty Acids Promote Post-Stroke Recovery in Aged Mice. Thank you both very much for joining me today. Dr Venu Venna: Thank you Cindy for having us. It's a pleasure. Dr Juneyoung Lee: Yeah, thank you for the opportunity. Dr Cindy St. Hilaire: It's a wonderful paper. Actually I really enjoyed the nice graphical abstract, that really made a good visual of what this papers about, so I encourage everyone to go take a peek at that. Could you introduce yourselves and tell us a little bit about your lab group? Dr Venu Venna: Yeah, sure, I'm Venu Venna, it's my third year at McGovern Medical School UT Health, and we are a part of a large research group in the Department of Neurology here. This is headed by Dr Louise McCullough. She's also a co-corresponding author on this paper. Unfortunately she's not here today, but it's basically her idea and her initiative that led us to drive this huge project. We are very excited to share with you more details today. Dr Juneyoung Lee: Hi, my name is Juneyoung Lee. I'm postdoctoral fellow here and I'm working with Dr McCullough and Dr Venna. Dr Cindy St. Hilaire: So this manuscript is testing the general hypothesis that the gut microbiome can influence stroke recovery but before we dig into the details of your study, can you give us a little bit of background about what the microbiota gut brain axis is? Dr Venu Venna: That's a great question. Thank you for asking that. So recent advances in 16S sequencing, metagenomics, and metabolic analysis lead us to specifically identify the role of gut microbiota. We have... Everybody consists of large number of microbiota in the gut, so particularly the microbiota's role is largely remains unknown, as of now. The recent advances helped us to understand whether it's for communication of the microbiome, how it actually influences our health, and how the metabolites that are released by the microbiota can actually influence the brain-gut. So this is where the concept of microbiota gut-brain axis continues to evolve and we rely on 16S metagenomics, as well as metabolomics to understand if the microbiome itself has a specific role in the stroke recovery and stroke in this paper. Dr Cindy St. Hilaire: Great, so I know that previous research by you specifically, and also you mentioned your fellow corresponding author, Dr Louise McCullough, your prior work has shown that stroke can cause aberrant changes in the gut regarding things like motility, permeability, activation of gut-immune cells. So this to me suggested that aberrant signaling can come from the brain and affect the gut, but your study is kind of now flipping that. You want to ask the question is changing the gut microbiome after the stroke also beneficial? So there's kind of a chicken and egg type conundrum going on. Is there a preceding event, is it the stroke that alters the gut microbiome primarily, or is the gut microbiome maybe deficient in different people and therefore their stroke outcomes are different? Dr Venu Venna: Yeah, I mean this is a very new emerging field and what's very interesting about this is the brain gut microbiota axis, it's a bi-directional axis. In this case, what we think is if we have a stroke, it may actually directly influence the gut. There is a brain-gut axis. At the same time, the changes in the microbiome can actually trigger an inflammatory state where it can actually contribute to the worst stroke outcomes. It's a chicken and egg relationship as you rightly mentioned, but at the same time what is not known is whether if we can simply manipulate the microbiota, can you actually improve the stroke outcomes or can you improve the age associated outcomes? Because what we found in previous studies is age itself causes changes in the microbiome. Dr Cindy St. Hilaire: Interesting, so just being young or old, if you were to compare those microbiomes of old individuals and young individuals, you see differences that are I guess negatively impactful on things like stroke and disease? Dr Venu Venna: That's exactly right, so the more imaging data coming out from the literature, not just our group, but all other groups, on humans and animal studies, do suggest that age itself is associated with changes in the gut microbiome. Dr Cindy St. Hilaire: So the overall goal of this specific study was to determine if replacing the gut microbiota of an older mouse with the microbiota from a younger mouse would help in the recovery after an ischemic stroke. Can you talk about the design of that study and the different aspects that you had to consider when designing these experiments? Dr Venu Venna: Yeah, absolutely. This was a great question. The initial experiments, like what we were trying to do before, was whether we can actually even manipulate the microbiome in an aged animal. In our previous study, what we did is we took a young animal and we transplanted the biome from an aged animal. We used a combination of antibiotics to actually deplete the existing biome and that's what gave us susceptibility to transplant. Once you transplant the biome into a donor from a host, so the biome can actually sustain for quite a bit of time. This gave us an opportunity to study the direct role of microbiome. Later, what we did was we subjected these animals to the stroke and then what we found is when we induced this stroke in an animal that received aged biome, despite being young, the animal that received aged biome, can itself contribute to the worst stroke outcomes and increased mortality. In this follow-up study, what we decided to do was can we even manipulate the microbiome after stroke? So this is particularly important because most of the clinical patients don't come into medical attention until after stroke. Transplanting the microbiome or even manipulating the microbiome after stroke can have a broader clinical relevance. In this particular study we decided to see if we can actually manipulate the microbiome after several days or several hours after the stroke happens. We decided to test if we can wait for three days. This is a particular time where we can actually see the infarcts get mature and all the injury in all groups of animals are same, and then we transplanted the aged animals with the young microbiome. So this gives us an opportunity to actually study the role of microbiome, independent of infarct. Meaning, all animals have a similar degree of injury, so now whatever the beneficial affects you are seeing because of the microbiome transplant, are potentially due to, not because of the size of the injury, because they have a smaller injury they have better recovery, but it's basically because their infarcts are the same and whatever you're seeing is because of the manipulation of the microbiome. Dr Cindy St. Hilaire: Interesting. Juneyoung, would you like to tell me a little bit about what you found then? Using these interesting fecal transplant models, what are the key results that you found in this study? Dr Juneyoung Lee: Great question. As Dr Venna explained, we treated young biome to aged stroke mice, after stroke. We found that young biome contributes to better behavior outcomes and they regulate the immune system in the brain and the gut and increase the short term brain-gut axis in the aged stroke recipient mice. One interesting finding is that we found dominant T-cells, which are very small number of T-cells in the host, but they secrete proinflammatory cytokines which is IL-17. Cytokines exacerbate new inflammation in the brain so if we treat the young biome, we found that the level of proinflammatory cytokine IL-17 decrease cytokines compared to aged biome. Dr Cindy St. Hilaire: You also focused on short-chain fatty acids, SCFA producing bacteria. What is it about these short-chain fatty acids that are beneficial and what are the signaling pathways that you found to be activated or things that were present that helped to promote better stroke recovery? Dr Juneyoung Lee: Short-chain fatty acids are key metabolites produced by bacterial fermentation of dietary fiber in the gut. These are suspected to play an important role in microbiota gut-brain crosstalk. Also, in our previous study we found that young fecal biome has higher levels of short-chain fatty acid compared to aged biome so we think that the short-chain fatty acid has a beneficial role in our mild level stroke. Dr Cindy St. Hilaire: So are you focusing more on identifying the metabolites or trying to move into humans? What do you think the next step of this vein of research is? Dr Venu Venna: So what we think is right now, this is a very interesting and fascinating finding, even for us. We're trying to understanding what other metabolites could be involved and what other ways as you previously asked, what other pathways these bacteria itself are triggering or contributing to actually enhance this recovery, that's what we are seeing from the young microbiome. As a future direction, we are also seeing if this transplant of biome can have a broader therapeutic relevance, meaning is it only specific to the stroke related outcomes or can it be beneficial in large settings of other age relate diseases like what we are seeing, again as I mentioned before like age related diseases such as... Many age related diseases like cognitive dementia, or Parkinson's disease, any neurodegenerative disease. Dr Cindy St. Hilaire: Well thank you, Drs Venu Venna and Juneyoung Lee for joining me today. I really appreciate it and congratulations again on this wonderful story. Dr Venu Venna: Thank you very much for having us, Cindy, and for this work I would like to acknowledge the funding agency. This work is funded by NIH and also the American Heart Association, both for my Scientist Development Grant and also as well as for Juneyoung Lee's postdoctoral fellowship. This funding helped us to perform these highly innovative studies in gut microbiome axis. Dr Cindy St. Hilaire: Wonderful. Yes, well, we love seeing AHA funded research published in AHA journals, so thank you. Right so now we're going to have our interview with the BCVS Outstanding Early Career Investigator Award competition finalists. I have with me today, Shyam Bansal from Ohio State University, Emmanouil Tampakakis from Johns Hopkins University, and Yang Zhou from the University of Alabama, Birmingham. So congratulations to all of you for being recognized for your outstanding science. These topics are great. The timing of T-cells activity in chronic heart failure, sympathetic neuron signaling, circadian genes and cardiomyocyte proliferation, and the identification of a transcription factor that helps promote maturation of reprogrammed cardiomyocytes. So, Dr Bansal, your abstract that's recognized, is titled Novel Inhibitors For Temporal Modulation Of T-lymphocytes During Chronic Heart Failure. Where was this study conducted and where are you now? Dr Shyam Bansal: Right now I'm at Ohio State University. I joined here in July 2019 and I've been setting up my lab. While doing that, we conducted all this work. This work, most of it is done here, and we have been looking to identify certain inhibitors that can be used for T-cell modulation. Dr Cindy St. Hilaire: Excellent so why should I care about T-cells in the heart? And what did you all find in this paper? Dr Shyam Bansal: The right question is why shouldn't you? T-cells are coming out to be involved in almost every chronic disease. We have heard about CAR T-cell therapy. Recently it revolutionized the whole cancer research field. The heart failure and cardiovascular diseases has also been realizing the importance of T-cells. They're important in a way because they are kind of a two-edged blade. They are protective because we need them to initiate those wound healing cascades so the tissue can regain its original function. But then, too much activation of T-cells can be injurious and lead to autoimmune reactions. In 2017 I published a paper during my postdoc with Dr Sumanth Prabhu at UAB where we showed that these T-cells get activated during chronic heart failure. It's a double-sided activation to get activated immediately after injury but then they go down and they come back again, during chronic heart failure. That's where the two-edged blade comes into picture. If you alter these T-cells during this acute phase, during the cardiac infarction, the animals always do worse, right? They are protective because they are needed for wound healing pathways. Dr Cindy St. Hilaire: We can't just stop them at the start, we need to fine tune. Dr Shyam Bansal: Yes. Dr Cindy St. Hilaire: So what's this temporal aspect you looked at? Dr Shyam Bansal: So that's what we found in my postdoc in 2017 paper. If you inhibit these during the chronic phase, in mouse, in rodents, it was whole weeks after infarction, then you can actually stop maladaptive remodeling. You can complete shut it down, it doesn't get better but you at least shut it down completely. We did those studies by using some antibodies, again CD4+ T-cells, and using genetic mouse models. Dr Cindy St. Hilaire: So do you think anything that you found can quickly or soon translate to humans? Dr Shyam Bansal: That's exactly what we did after we came here, right? So we compared what happens during this chronic heart failure, what happens to these T-cells. We identified one molecular pathway that's associated with receptor signaling, being activated in these T-cells. The interesting thing is, these T-cells came from male mice, not from females. Still, they had strong activation of the surge in receptor signaling. We found a drug molecule that can activate another pathway that inhibits this pathway, so indirectly we're able to inhibit this pathway. We did those studies and found that we can actually stop T-cells from getting activated during chronic heart failure and when we do that, this drug can actually, again, inhibit left ventricular remodeling significantly. Dr Cindy St. Hilaire: Wow. Dr Shyam Bansal: And if you give this drug early in myocardial infarction, again, animals died. Dr Cindy St. Hilaire: It's going to be very important to fine tune when that drug could potentially be administered to humans. Dr Shyam Bansal: Yes, and that's the first drug in our knowledge that can actually target specific antigen activated T-cells. Dr Cindy St. Hilaire: Super exciting, well congratulations again. Well done and well earned. Dr Tampakakis, your study is titled Sympathetic Innervation Negatively Regulates Postnatal Cardiomyocyte Proliferation Through Circadian Genes. So where was this conducted and what position are you in now? Dr Emmanouil Tampakakis: This research was conducted at Johns Hopkins University and I'm currently part of the... I'm Assistant Professor within the Division of Cardiology in the School of Medicine. Pretty much for my curiosity and the fact that we know a lot about the role of neurons for adult heart disease but we really don't know what much about neurons are doing at the neonatal stages in heart development. We know at least in preterm babies where the innervation is really affected, some of them do develop changes in their heart geometry, and there might be a role there, plus there is some data to suggest that the autonomic nervous system does manipulate or does affect the neonatal heart regeneration. The role of neurons to me was really intriguing. Dr Cindy St. Hilaire: So this is linking together sympathetic nervous signaling, circadian genes, and postnatal cardiomyocyte proliferation. Why do I care about all these things fitting together? Dr Emmanouil Tampakakis: Yes, so apart from the fact that it's fascinating knowing that each individual organ has in their body its own circadian genes that regulate actually, several functions. Without being affected by the central nervous system and what's happening in the hypothalamus, which to me is really fascinating, is we really don't know much about what actually regulates and synchronizes the circadian cycle of the heart. We, in this study, showing that actually the innervation that happens in neonatal stages, already aaffects how certain genes are circulating within the heart. That appears to be through one of the adrenergic pseudoephedrine way that the sympathetic nerves are secreted. Again, by affecting this, we are showing that there is more proliferation of neonatal cardiomyocytes which can be important for disease at later time points, and we're also showing that if you mess up two specific circadian genes, Period 1 and Period 2, that are transcription regulators, and are some of the masterminds of this phenomenon, you can actually still affect neonatal cardiomyocyte proliferation which can be important for diseases like heart degeneration and whether we're thinking about manipulating other pathways to induce more regeneration and induce healing in the heart. The novelty of our work is we see that there's a link between that cell cycle and the circadian genes, at least at neonatal time points when myocytes proliferate a little more. Dr Cindy St. Hilaire: So neat. Congratulations again, it's a wonderful story and I'm really happy it's being recognized. And Dr Zhou, you're being recognized for your work that's titled TBX20 Activates Cardiac Maturation Gene Programs Promoting Direct Human Cardiac Reprogramming. So where was this study started and where are you now? Dr Yang Zhou: So I started as an Assistant Professor of Biomedical Engineering at UAB in January 2019. Before I moved to Birmingham, I did my postdoc training at the University of North Carolina at Chapel Hill in Dr Li Qian's lab. I basically studied direct cardiac programming which directly convert non-myocyte cell type to the functional cardiomyocytes. I did a lot of work and found the epigenetic barriers and I find that the features of these direct programming cells and almost in the mouse cells, but we know that we have to move that to the human cells, so then when I moved to Birmingham and then I studied the cardio programming from the cells. Dr Cindy St. Hilaire: Excellent, so your study is looking for ways to really kind of push the direct conversion of cardiomyocytes into a more fully differentiated state. Why is that an important question and what did you find in this study? Dr Yang Zhou: Yeah, it is still challenging to gather a functional beating cardiomyocytes from human fibroblast by the direct reprogramming method. We want to get the functional cardiomyocytes to do the cell therapy. Also this method has promise to do the in situ heart regeneration because we use the transcription factors we can inject these factors to the injured heart then directly convert those cardiac fibroblasts into the cardiomyocytes. So we have to study, we have to know how to get the functional work that cardiomyocytes. Dr Cindy St. Hilaire: That is so neat. So really you're hoping to harness those fibroblasts in the heart that everyone kind of ignores because they're not contractile and you're hoping to really take them and transition them to these fully functioning beating cardiomyocytes. Dr Yang Zhou: Right, so we know that the stuff we are coding are very important for the contractility, the myocyte contractility, so we find that a lot of missing protein expression in the current direct programming cells, so my hypothesis is they might be missing key regulators and can promote expression of those coding in the genes. My computational analysis of the transcription data, I find that this T-box, transcription factor Tbx20, that can highly promote those unexpressed genes in the reprogrammed human cardiomyocyte. Dr Cindy St. Hilaire: That's wonderful. Well congratulations again on some excellent work. So I want to ask you all, early career question, you're all within I think the first couple years of starting up your lab, and we're in the midst of a pandemic which means none of us are in the labs. Maybe staff is at reduced numbers, but first, how's it going? And second is, you're kind of still fresh in terms of transitioning. So I'm wondering if there's any one piece of advice that you'd like to share with maybe someone who's in the middle of transitioning or just about to. Or if there's something you wish you knew ahead of time that you'd love to tell your pre-faculty self? Dr Emmanouil Tampakakis: Yeah, I don't know if I can give advice, already I think I'm too junior to do this. I would say that- Dr Cindy St. Hilaire: What, too traumatized? Dr Emmanouil Tampakakis: Maybe. Probably, or will be traumatized, but I would say for me at least, the things that kept me sane during this is my son, who's three and a half years old and lives in a complete different world, so that helps me balance what's happening out there. Dr Cindy St. Hilaire: That's so important. Dr Emmanouil Tampakakis: Probably some good alcohol at the end of the day but both those two things combined actually helped me maintain my sanity. In terms of advice, I would say to try to enjoy science. Try to stay focused and productive and at the end of the day, enjoy what you do. I think that if you are creative and if you like what you do, find the right people to collaborate and work with and you can hope that you will do well. Dr Cindy St. Hilaire: I agree. Excellent advice. Dr Shyam Bansal: I also have two kids, three years and eight years old, so we were at home for two and a half months or so. I think those kids were really helpful in keeping my sanity because the weather was getting better so we had to put in a swing set for them, get some play items and stuff, so they kept me busy. That was good that way. The advice that I will have for junior investigators is be collaborative. Try to see how you can help others because when you help others, others are ready to help you as well. Remember science is a collaborative field, the more you collaborate with people, the more you get to know many more stuff. Dr Cindy St. Hilaire: I think that's so important. Dr Shyam Bansal: I was able to get done a lot of whatever work we presented. I was able to set up my lab, get some work done, and be at a position that I was able to summit my first abstract to BCVS for my independent own work, just because I had good collaborations here. I had good people who helped me stand on my feet and obviously I was working and helping them also. Dr Cindy St. Hilaire: Yeah, and it also sounds like you have good colleagues so that's another key to it. Dr Shyam Bansal: Yeah, I'm really lucky that way. Our whole department is really great. We have several senior faculty who are always ready to help us out in whatever issues we have, personal, professional, scientific, they're always here for us. Dr Cindy St. Hilaire: That's great. Yang, how about you? Dr Yang Zhou: I think the pandemic is very challenging for our junior faculty and for research and career developments but we have to balance between the work and the family, like kids. You might have an issue because we have two PIs in our lab. Dr Cindy St. Hilaire: Oh gosh. Dr Yang Zhou: Yeah, but I learned a lot these two years before this position. I think the most important thing I feel like is you have to talk to people. You always can find people that can help you to find answers. You need a mentor because they are more senior, they have more experience, even in this pandemic, if you find someone to share even just your feelings, that's very helpful. Dr Cindy St. Hilaire: We're almost lucky that this happened now where we can have platforms like Zoom, and Adobe Connect, where we can have these virtual conferences because at least on all the different committees I'm on, ATVB and BCVS, we can have these discussions and break-out sessions, so I think it's really... We're lucky it's happening now and not 1997 when there's no video. Dr Yang Zhou: Concerns... We all feel that the University and the Department, they all responded very quickly and they have much more support here than before. Dr Emmanouil Tampakakis: As a more senior, what advice can you give us as a more senior person? Dr Cindy St. Hilaire: Oh gosh, more senior? Well thank you. My advice? I definitely agree on the collaboration, I think that's key. Finding sponsors is equally important, someone who's going to go to bat for you. Finding a safety net where you can send someone a half-baked game page and have them tell you just how bad it is and be honest and be willing to give you that kind of critical feedback is really important. Building your network is key, and getting involved in societies and getting people to know you independently from your former mentor, I think is really critical. Yes, you want to collaborate but you also got to make sure that you have your own path in the sand, to make sure you can move forward independently, and have fun while you're doing it, like you said. Great, well I wish you all the best of luck. Congratulations again on being recognized and I'll see you on the BCVS webinar. That's it for our highlights from the late July and early August issues from Circulation Research. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and on Instagram with the handle @CircRes and #discoverCircRes. Thank you to our guests, Drs Venu Venna and Juneyoung Lee, and to the BCVS Outstanding Early Career Investigator Finalists, Shyam Bansal, Emmanouil Tampakakis, and Yang Zhou. This podcast is produced by Rebecca McTavish and Ishara Ratnayake, edited by Melissa Stoner, and supported by the editorial team at Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research.  

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin Xiaohang Qiao,......Jacques NeefjesProceedings of the National Academy of Sciences Jun 2020, 117 (26) 15182-15192; DOI: 10.1073/pnas.1922072117https://www.pnas.org/content/117/26/15182 Jocelyn Kaiser. New forms of ‘red devil’ cancer drug could spare hearts https://www.sciencemag.org/news/2020/07/new-forms-red-devil-cancer-drug-could-spare-hearts     Not Medical Advice or Opinion

Oncology Meds. Chemotherapy. Doxorubicin, cisplatin, cyclophosphamide, vincristine, bone marrow suppression. Free quiz & full course at https://Simplenursing.com/nursing-school  Pharmacology Master Class - 100 videos not on YouTube - Try it for Free!    Pharmacology Master Class - Try it for Free: https://Simplenursing.com/nursing-school  100 videos not on YouTube    FREE Access to new app + 1,000 videos not on youtube!  https://Simplenursing.com/nursing-school   NCLEX FREE TRIAL:  https://simplenursing.com/NCLEX   STAY IN TOUCH

Commentary by Dr. Ana Barac

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.08.139667v1?rss=1 Authors: gong, h., Yuan, N., Shen, Z., Tang, C., Shipp, S., Qian, L., Lu, Y., Andolina, I. M., Zhang, S., Wu, J., Yang, H., Wang, W. Abstract: Rapid and efficient gene transduction via recombinant adeno-associated viruses (rAAVs) is highly desirable across many basic and clinical research domains. Here we report vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated gene expression in cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time-period examined and detectable at just three days post-transfection. This enhancement showed serotype generality, being common to rAAV serotypes 2, 8, 9 and PHP.eB tested, and was observed both locally, and at remote locations consistent with doxorubicin undergoing retrograde axonal transport. All these effects were observed at doses matching human blood plasma levels in clinical therapy, and lacked detectable cytotoxicity as assessed by cell morphology, activity, apoptosis and behavioral testing. Altogether, this study identifies an effective means to improve the capability and scope of in vivo rAAV applications, accelerating and augmenting gene transduction at doxorubicin concentrations paralleling medical practice. Copy rights belong to original authors. Visit the link for more info

Commentary by Dr. Paul Burridge

Commentary by Dr. Anju Nohria

ONS member Christine Rimkus, RN, MSN, AOCN®, clinical nurse specialist for the Siteman Cancer Center at Washington University in St. Louis, MO, and member of the St. Louis ONS Chapter, joins Chris Pirschel, ONS staff writer/producer, to discuss doxorubicin—otherwise known as the red devil—chemotherapy administration, what nurses need to know about vesicants in practice, and how to support and advocate for patients receiving doxorubicin treatment. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons: By Attribution 3.0 Episode Notes: Check out these resources from today's episode: Complete this evaluation for free nursing continuing professional development. Outpatient Oncology Drug Series: Doxorubicin Is the Infamous Red Devil The Case of the Vexing Vesicant Chemotherapy Extravasation: Establishing a National Benchmark for Incidence Among Cancer Centers Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice Understanding and Managing Oncologic Emergencies: A Resource for Nurses (Third Edition)

  Episode 278 is an all inclusive guide to kidney anatomy, health, bloodwork, and MORE for physique and performance based athletes! First I dig into some basics on kidney anatomy and function before moving into some considerations for athletes looking to get bloodwork done to track kidney health, and all before ending with practical application on how to maintain kidney health while pushing for your goals! Also, theres a few references I'll provide below for those looking to take things further!   REFERENCES Adelstein RS, Sellers JR. Effects of calcium on vascular smooth muscle contraction. The American journal of cardiology. Jan 30 1987;59(3):4b-10b.   Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, . . . Nielsen S. Aquaporin water channels--from atomic structure to clinical medicine. The Journal of physiology. Jul 1 2002;542(Pt 1):3-16.   AHA. American Heart Association. Kidney Damage and High Blood Pressure. Available at: http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/WhyBloodPressureMatters/Kidney-Damage-and-High-Blood-Pressure_UCM_301825_Article.jsp. Last updated 9/11/2014a. Accessed 8/10/2014.     Akinwusi PO, Oluyombo R, Ogunro PS, Adeniji AO, Okunola OO, Ayodele OE. Low dose aspirin therapy and renal function in elderly patients. International journal of general medicine. 2013;6:19-24.   Al-Awqati Q, Barasch J, Goldman L (ed.), SchaferAI (ed.). Goldman's Cecil Medicine, Twenty-Fourth Edition. Chapter 117: Structure and Function of the Kidneys; 716-720. Copyright 2012 Saunders, an imprint of Elsevier, Inc. Available at: www.clinicalkey.com Accessed: 6/9/2014.   Alpern RJ, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. American journal of kidney diseases : the official journal of the National Kidney Foundation. Feb 1997;29(2):291-302.   Amodu A, Abramowitz MK. Dietary acid, age, and serum bicarbonate levels among adults in the United States. Clinical journal of the American Society of Nephrology : CJASN. Dec 2013;8(12):2034-2042.   Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney international. Jun 2013;83(6):1010-1016.   Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, and Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes. 2003;52(8):2110–20   Bae EH, Lee J, Ma SK, et al. alpha-Lipoic acid prevents cisplatin-induced acute kidney injury in rats. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2009;24(9):2692–700   Balakumar P, Bishnoi HK, Mahadevan N. Telmisartan in the management of diabetic nephropathy: a contemporary view. Current diabetes reviews. 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Food Funct. 2012;3(12):1251–64     Davis KE, Prasad C, Vijayagopal P, Juma S, Imrhan V. Advanced Glycation End Products, Inflammation, and Chronic Metabolic Diseases:Links in a Chain? Critical reviews in food science and nutrition. Sep 26 2014.   De la Fuente M, Hernanz A, Viniegra S, Miquel J. Sulfur-containing antioxidants increase in vitro several functions of lymphocytes from mice. International immunopharmacology. Jun 2011;11(6):661-669.   Debreceni B, Debreceni L. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. Cardiovascular therapeutics. Jun 2014;32(3):130-138.   Dempsher J. The nerve impulse in the axon--a new theory. Acta biotheoretica. 1981;30(2):121-137.   Di Vito R, Sirolli V, Amoroso L, Bonomini M. [Nephrotoxicity induced by chemotherapy]. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. May-Jun 2011;28(3):296-304.   Dong JY, Xun P, He K, Qin LQ. 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Giuseppina Milano, Centro Cardiologico Monzino, Italy speaks on "Doxorubicin and Trastuzumab Regimen Induces Biventricular Failure in Mice". This movie is part of "UltraSound imaging in cardiac and vascular medicine: from pre-clinical to clinical studies" Course, 21-22 February 2019, ICGEB Trieste, Italy.

Now it's time to start fighting this thing. My chemotherapy would be every “RCHOP” (Rituxan, Cyclophosphamide, Doxorubicin, Oncovin, Prednisone) every twenty-one days and Neulasta. --- Support this podcast: https://anchor.fm/josalynscancerstory/support

This JCO Podcast provides observations and commentary on the JCO article “Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study” by Bates et al. My name is Joseph Carver, and I am the Chief of Staff at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pennsylvania. My specialty is cardio-oncology. It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.   It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.  Total dose delivered does not reflect specific cardiac exposure.  This has led to report the mean heart dose that is the percent cardiac volume within the radiation fields.  For most treated patients, discovery of anthracycline cumulative dosing is easily abstracted and straightforward. For modern therapeutic radiation, however, historical mean heart dose or other cardiac dosimetric parameters have not been traditionally reported and may be more difficult to obtain. This has led to a lack of consensus about the cardiovascular risk when the total dose is 5-year survivors who were treated for a variety of cancers at a median age of 7 years.  Evaluation occurred at a median follow-up of 20.3 years with a median attained age of 27.5 years.  Late cardiac risk was compared to 5,046 untreated siblings.  For each survivor, radiation fields were reconstructed on age-specific phantoms to calculate estimated mean heart dose and the percent of heart volume receiving at least 5 Gy (low dose) and 20 Gy (higher dose).  Doxorubicin-equivalent doses were similarly abstracted.   Toxicity parameters were any cardiac disease, coronary artery disease and heart failure.  They found a cumulative incidence of cardiac disease, 30 years from diagnosis of 4.8% (95% CI 4.3-5.2). There was a dose relationship between mean heart dose and all parameters.  Both low-moderate doses (5-19.9 Gy) to a large volume of the heart (>50%) and higher doses (≥20Gy) to small cardiac volumes (0.1-29.9%) were associated with an increased risk of cardiac disease. Heart failure drove the risk of high doses to small volumes while CAD drove the risk of low doses to large volumes.   Similarly, they reconfirm the relationship between cumulative anthracycline dosing and any cardiac disease with an increased risk for those treated at a younger age (≤ 13 years of age).  An increased relative risk for any cardiac disease was also present with any anthracycline exposure (0.1-

  Welcome to another episode of Biotechnology Focus radio! I am your host – Michelle Currie – here to give you the rundown on what is happening in biotech across the country from coast to coast. There have been some interesting developments in the last couple weeks that are changing the scope of the life sciences industry. Some of which I get the pleasure to share with you today. As a first for Canada, Concordia University now houses a facility that will change how synthetic biology research will be conducted; Bioasis Technologies’ promising drug development may have found a way to cross the blood-brain barrier; the Centre for Commercialization of Antibodies and Biologics invests in ImmunoBiochem to advance their therapeutic candidate; and the Canadian government, as well as other investors, allocate $8.8 million to three projects in Ontario.   Keep on listening to find out more details!  +++++  A new facility at Concordia is about to change history. It will house robots that will bring a whole new concept of speed and scale to synthetic biology research.  The Genome Foundry is the first Canadian laboratory of its kind, and amongst only a handful at leading institutions around the world. By automating notoriously labour-intensive lab work, it will eliminate bottlenecks in a rapidly evolving field where the design principles of engineering fuse with the tools of biology to create meaningful synthetic biological systems.  Christophe Guy, vice-president of Research and Graduate Studies at Concordia says that the Genome Foundry solidifies Concordia’s position as the Canadian leader in synthetic biology research and will enable their scientists to work at the cutting-edge while facilitating partnerships with other institutions. Given that Concordia researchers are already engaged internationally in defining the future of this field, they are eager to witness how this new facility will support the transformative work being done at the university.  At the moment, much of the lab work done by synthetic biologists involves moving and combining small amounts of liquids and cells. The Genome Foundry’s robotics will allow for speed and absolute precision, thus greatly increasing the variety and number of experiments that can be completed, and the accuracy with which they can be reproduced.  The Genome Foundry was established with funds from the Canada Foundation for Innovation and the government of Quebec and is part of Concordia’s synthetic biology hub along with the Centre for Applied Synthetic Biology (CASB), the SynBioApps NSERC CREATE program and the soon-to-be-inaugurated District 3 Innovation Centre science hub.  Vincent Martin, co-director of the Centre for Applied Synthetic Biology says that they are thrilled to open the doors of our Genome Foundry. That this is a monumental addition to Canada’s synthetic biology ecosystem. It empowers researchers to navigate uncharted waters alongside international colleagues, and to incubate the future leaders of the field.  The Centre for Applied Synthetic Biology aims to develop high-value applications in human health, agriculture, chemicals and environmental technologies. It also provides a broad range of unique opportunities — such as the recently announced NSERC CREATE SynBioApps program — for training leading experts in the field.  Launching this technology platform also marks Canada’s participation in the next generation of synthetic biology, with Concordia now engaged in directing how this infrastructure will be developed and used on a global scale.  This facility will have real world, potential life-saving capabilities that deliver an innovative scientific approach to create genetic blueprints for individuals, bring more knowledge to researchers on a faster scale, and help physicians diagnose, treat and prevent their patients from contracting future diseases.  +++++  With neurological diseases predicted to rise exponentially across the globe, whether resulting from the extension of life expectancy or aging populations, more novel solutions are necessary so that health care can stay ahead of the game.  Neurological diseases, disorders and injuries – such as Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, brain tumours, and Parkinson’s disease – are some of the leading causes of disability amongst the Canadian population that take a toll not only on the patient and the Canadian health care system, but also have a significant economic impact.  To date, these neurological diseases and disorders have been largely incurable and tend to worsen over time, typically involving invasive procedures by scientists and researchers as they attempt to penetrate the blood-brain barrier. Remarkable as the blood-brain barrier is to neuroscience, it is extremely fickle and highly selective, restricting the paracellular diffusion of water-soluble substances from the blood to the brain. Despite it being nature’s evolutionary way of protecting humans’ greatest asset, it does not come without its faults. Its defensive properties impede the way for medicinal compounds to penetrate the barrier and deliver the potential life-saving properties to their destination point.  Statistics have shown that 1 in 6 will acquire a neurological disease, totalling about 1.25 billion people worldwide. It is for this reason Canadian company Bioasis Technologies Inc. is determined to deliver effective treatments to patients who suffer from one of these diseases.  Vancouver-founded Bioasis has undertaken this challenge by focusing on a single goal: revolutionizing science by transporting therapeutic payloads across the blood-brain barrier and into the brain. They have developed and are in the process of commercializing their proprietary brain delivery technology, the xB3 platform, to make life-saving drugs brain-penetrant and deliver those therapies at a therapeutically relevant dose.  Inception of the company began back in 2007 when researchers discovered an extremely large peptide that was capable of crossing the blood-brain barrier with a substantial amount of cargo. The team did a couple of experiments with Doxorubicin in mice models with cancer that positively showed higher survival rates and became the first proof of concept. The also acquired Trastuzumab data whereby they transferred Herceptin across the blood-brain barrier in sufficient quantities to reduce the number of tumours.  Although researchers have been speculating about less invasive methods that will penetrate the barrier, Mark Day, the president and chief executive officer of Bioasis, comments that the key thing if you have brain cancer is that the only therapeutic benefit will come from a direct infusion into the brain – like drilling a hole in the head – and while some people are trying to inject into the spine and pump it into the central nervous system, none of it has worked. The brain methods do work, so there is at least some data if you inject it that you can get it approved for efficacy for small groups of patients.  Recently, MedImmune, a wholly-owned subsidiary of AstraZeneca, did an independent validation of Bioasis’ xB3 platform technology that transpired incredible results. The study found that the xB3 fusion protein maintained the systemic pharmacokinetics of its payload and had significantly improved and sustained brain exposure of the payload molecule. It provided evidence that Bioasis’ platform technology was recombinant and chemically conjugated drugs across the blood-brain barrier to increase brain exposure.  These data and validation from MedImmune provide promising results that it will work in a phase 1 study. Bioasis figured out that once they attached Trastuzumab to 12 active amino acids (peptide 12aa), 10 times the amount of the drug passed through the blood-brain barrier. Mark Day adds: “What is really important is that once the drug is in the brain it hits the tumour. Looking at these results you can see that there are significant therapeutic doses in the brain and in controlled regions. This shows us that the drug gets into the brain, it gets to the site of action, and binds to those specifically where there are HER2 positive cells.”  Bioasis has four main programs:  xB3-001: Brain Metastases, which is the most common form of brain cancer in adults and is often fatal due to anti-cancer drugs being unable to pass the blood-brain barrier, and is also the program that will progress first to human trials in 2019;  xB3-002: Glioblastoma, one of the most aggressive cancers that originates within the brain, with 80 per cent of diagnosed primary malignant brain tumours as malignant gliomas. It is considered the deadliest form of brain cancer due to its high infiltration of surrounding brain tissue. This program is being done in collaboration with Minerva in Copenhagen;  xB3-007: Neurodegenerative diseases, which entail a progressive loss of function by the neurons in the brain and in being diagnosed at an alarming rate partly due to an aging population; and  xB3-008: Lysosomal storage diseases, which are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies.  If the xB3-001 and xB3-002 programs are successful, it would be the first time in human history that medicine for cancer has been properly received into the brain without having to drill into the patient’s head. This will be a breakthrough in science and open the doors to a floodgate of scientific possibilities.  Bioasis’ technology platform has been so efficacious that there simply have not been any competitors that have been able to keep up. The receptor with which they work with is ubiquitous to the blood-brain barrier walls, providing more possible passageways for medicine to penetrate through. This receptor, even in its natural form, is critical in cleaning out harmful tissues in the brain like Alzheimer’s disease for example and is necessary to maintain brain integrity.   Mark Day adds that the other thing that differentiates them is how they develop drugs. They know that if you engage the target and prove that the target engagement drives biologic effect – to schizophrenia that would be a lowering of dopamine – then you have a good sense of patient population. So, for some of these diseases, there is a very strong genetic basis to them and subsequent diseases that gives them the mechanism to recruit the patient who is most likely to benefit from the medicine in the first tranche.  The proof of principal in the first point, get the proof of concept, on the back of a positive proof of concept then you would go earlier into the diseases. That’s what they can do with our last two neurodegeneration products. Basically, they go into a smaller niche indication, get the proof of concept and then expand it into other disease areas. That’s been the strategy.  With recent editions to their scientific advisory board and looking ahead to put them in the best financial position for Nasdaq, the future looks promising for this biotechnology company. Penetrating the blood-brain barrier has been an arduous task, but if Bioasis is successful, their technology will revolutionize the treatment for neurodegenerative diseases and brain tumours, potentially slowing the progression of disease, and maybe someday offer a cure.  +++++  The Centre for the Commercialization of Antibodies and Biologics (or CCAB) provides a new investment to help advance ImmunoBiochem’s novel breast cancer therapeutic candidate one step closer to the clinic. The agreement marks a first for CCAB as part of its new business strategy, which aims to attract investment to create successful life sciences companies in Canada. CCAB will develop ImmunoBiochem’s lead candidate towards regulatory filings, and merge their business acumen with its research and technical expertise to support the co-development of new biological therapeutics.  CCAB CEO Robert Verhagen says that today’s announcement marks the beginning of a very exciting period of growth. The agreement with ImmunoBiochem is a natural extension of an already fruitful partnership and that they are looking forward to helping the company get to the next crucial stage in the development of this promising anti-cancer therapy. As CCAB continues to expand its mission in this space, they plan on establishing similar partnerships with other emerging companies in the near future.  ImmunoBiochem is developing novel potentiated biologics to treat triple-negative breast cancer (TNBC), an aggressive form of breast cancer for which there are currently no targeted biological treatment options. Earlier this quarter, ImmunoBiochem secured an additional private investment to support its pipeline and entered into a license agreement with the University of Toronto for novel therapeutic antibodies.  ImmunoBiochem’s CEO Dr. Anton Neschadim says that ImmunoBiochem’s highest priority is to make new treatment options available for patients with this difficult-to-treat breast cancer. They have made significant progress and have validated their approach in vivo. CCAB has been tremendously supportive of their work and they are excited that this new agreement will help them advance their lead candidate even further.   Breast cancer is the most common cancer among Canadian women and is the second leading cause of death from cancer. In 2017, 26,300 women were diagnosed with breast cancer and 5,000 women died from the disease. Triple-negative breast cancer accounts for up to 20 per cent of breast cancers and is one of the most heterogeneous diseases, comprising multiple breast cancer sub-types. Consequently, even highly promising treatments that are in late stages of the clinical pipeline are likely to only address the needs of a partial number of triple-negative breast cancer patients. ImmunoBiochem has developed therapeutic candidates that aim to close on this gap by overcoming treatment challenges associated with tumor heterogeneity.  Much of biological therapeutics distinguish cancer cells from normal cells based on proteins differentially expressed on their surface. In solid tumours, most such targets are heterogeneously expressed, impeding complete responses and driving resistance and relapses. ImmunoBiochem is focusing instead on selective targets in the tumour microenvironment that are broadly present and interact with all cells in a tumour, including tumour-supporting stroma. ImmunoBiochem has shown that this approach could be more effective and safer than conventional surface-targeted therapeutics.  This agreement between the two companies has the potential to lead to viable therapeutics that are sorely needed, especially for cancers that have a high rate of morbidity and mortality.  +++++  Genome Canada announces federal funding for seven new projects under the Genome Canada’s Genomic Applications Partnership Program (GAPP), three of which hail from Ontario. This will be driving $2.9 million of federal funding into the province and an additional $5.9 million from investments in the industry, government, and funding partners. For a total of $8.8 million, this could heed rewarding results.  The announcement was made by the Minister of Science and Minister of Sport and Persons with Disabilities. The Honourable Kirsty Duncan, at the Vineland Research and Innovation Centre.  Vineland is partnering with a team of University of Toronto researchers to develop genomics-based technologies that will induce broad-spectrum disease resistance in greenhouse vegetables, allowing new varieties of vegetables to thrive and reducing waste. This will give growers across Ontario and Canada a competitive advantage in a national industry that already generates more than $1 billion annually from retail sales and exports.  In another Genomic Applications Partnership Program project, researchers at McMaster University are partnered with Hamilton-based start-up Adapsyn Bioscience Incorporated to use its proprietary technology platform that combines genomic and metabolomic data with artificial intelligence and machine learning to redefine and accelerate drug discovery for novel treatments of a wide spectrum of diseases. This partnership secured significant foreign and domestic investment and is creating new high-tech jobs in Ontario.  The third Ontario-based Genomic Applications Partnership Program project announced brings together researchers at the Sunnybrook Research Institute and the University of Toronto with Canadian start-up Fusion Genomics to further develop novel infectious disease surveillance tools. Their technology is unique in its ability to detect and genetically characterize infectious viral pathogens through bioaerosols to serve as an early warning for disease outbreaks in both humans and agricultural animals. The development of this pre-emergence environmental detection technology will drive a paradigm shift in public health and animal welfare by offering complete genomic data to anticipate outbreaks, inform disease transmission dynamics and enable vaccine design and production.  Genomic Applications Partnership Program is a program that partners researchers with companies and other end-users who will apply their innovations with the goal of increasing and accelerating the positive social and economic impact of Ontario’s and Canada’s genomics R&D capacity. Since 2013, approximately $86.1 million, including co-funding has been invested in 23 Ontario-based Genomic Applications Partnership Program projects, fuelling innovations, spurring job creation and attracting foreign investment in Ontario’s health, agriculture & agri-food, fisheries, environment and natural resource sectors.  In such an emerging industry, there is nothing better than seeing companies and research succeed. With these recent investments, there is high hope that we will see encouraging results in the future.  +++++  Well that wraps up another episode of Biotechnology Focus radio! Thanks for listening! If you have a story or a story idea, feel free to contact me at press@promotivemedia.ca. Until the next time, from my desk to yours – this is Michelle Currie.

In 2014, Julie was diagnosed with Stage IIc ovarian cancer. After using conventional treatment and making changes to her diet and lifestyle, she was doing okay – until her car was hit by a semi truck. After a difficult year of  rehab and recovery from the accident, she discovered that her ovarian cancer had metastasized to her colon... Stage IV. After thoughtful research and consideration, and despite the pressure from her oncologist, Julie chose a different path. She chose to use integrative and natural therapies support her body's ability to heal and she restored her health. I know Julie’s perseverance and commitment to healing ovarian cancer will inspire you! Enjoy! Show Notes -Her cancer diagnosis and horrific treatment side effects [01:00] -A life changing encounter with a semi truck [04:23] -How a recurrence gave Julie a second chance at healing [07:03] -Building the perfect modality of therapies and diets [10:11] -Salicinium and mistletoe IV therapy [11:00] -Why it’s important to listen to your instincts & intuition [15:20] -Doxorubicin aka "Red Death" or "Red Devil" [16:11] -How Julie reached her ultimate goal [18:18] -Making fact-based decisions, not fear-based decisions [21:15] -Getting bullied by her doctors to do treatment [23:00] -How to look for the little clues from your doctor [25:48] -Balancing oxidative and anti-oxidative therapies [28:23] -Julie’s results: “nothing remarkable” [32:05] -Advise for the newly-diagnosed cancer patient [34:06] If you or someone you care about has cancer, make sure you download my free guide: 20 Questions For Your Oncologist. This is the guide that Julie used to get the answers she needed to make an informed decision about her treatment. Links from the article here: https://www.chrisbeatcancer.com/how-julie-healed-ovarian-cancer/ (((c)))

David A. Bluemke, MD, PhD, Editor of Radiology discusses three research articles and five review articles from the March 2018 issue of Radiology.ARTICLES DISCUSSED: Summary of High-Risk Breast Lesions: A Machine Learning Model to Predict Pathologic Upgrade and Reduce Unnecessary Surgical Excision. Radiology 2018;286(3):810-818 Summary of Generalist versus Subspecialist Characteristics of the U.S. Radiologist Workforce. Radiology 2018;286(3):929-937. Summary of Technical Developments: Zero Echo Time Imaging of the Shoulder: Enhanced Osseous Detail by Using MR Imaging. Radiology 286(3):960-966. Summary of March review articles on Free-Text Radiology Reports, Focal Liver Lesions: Computer-aided Diagnosis by Using Contrast-enhanced US Cine Recordings, Prevalence of Carotid Web in Patients with Acute Intracranial Stroke Due to Intracranial Large Vessel Occlusion, Cervical Internal Carotid Occlusion versus Pseudo-occlusion at CT Angiography in the Context of Acute Stroke: An Accuracy, Interobserver, and Intraobserver Agreement Study, and Assessment of Response to Transcatheter Arterial Chemoembolization with Doxorubicin-eluting Microspheres: Tumor Biology and Hepatocellular Carcinoma Recurrence in a5-year Transplant Cohort

Overview of doxorubicin from its Italian origins to its Red Devil alias. Uses and toxicities also discussed, of course.

Dr Calvo talks to ecancertv at ASCO 2015 about data from a Phase 1b study of the transcriptional inhibitor PM1183 in combination with doxorubicin in second line therapy in patients with small cell lung cancer (SCLC) The treatment induced objective responses in 67% of the patients, including 10% of them where all signs of cancer disappeared. Every patient with SCLC denominated primary chemotherapy-sensitive (their chemotherapy-free interval is more than 90 days) responded to treatment, including 18% of complete responses. In primary chemotherapy-resistant patients, where cancer was progressing within 90 days or less of previous chemotherapy, a remarkable 30% achieved a response. Notably, the treatment resulted in durable responses, with an overall progression-free survival of 4.6 months, which was 3.6 months in resistant patients. The most common adverse drug reaction was reversible myelosuppresion but no cardiotoxicity or drug-related deaths were observed.

Dr. Cathy Pietanza from Memorial Sloan Kettering Cancer Center discusses standard chemotherapy options for treatment of both sensitive and refractory small cell lung cancer (SCLC).

Dr. Cathy Pietanza from Memorial Sloan Kettering Cancer Center discusses standard chemotherapy options for treatment of both sensitive and refractory small cell lung cancer (SCLC).

Dr. Cathy Pietanza from Memorial Sloan Kettering Cancer Center discusses standard chemotherapy options for treatment of both sensitive and refractory small cell lung cancer (SCLC).

Adulte Weichgewebesarkome (engl. soft tissue sarcoma; STS) werden zu einer Gruppe seltener maligner und teilweise aggressiver Tumoren klassifiziert, die eine Tendenz zur Bildung von hämatogenen Fernmetastasen aufweisen. Die Kombination der Regionalen Hyperthermie mit einer Chemotherapie erwies sich in vorangegangenen Studien als eine vielversprechende Behandlungsoption beim lokalisierten Hochrisiko STS. Es wurde gezeigt, dass eine neoadjuvante Chemotherapie mit Regionaler Hyperthermie bei diesen Sarkomen das Tumoransprechen, das lokale progressionsfreie und das krankheitsfreie Überleben im Vergleich zu einer alleinigen Chemotherapie signifikant verbessert. Auf zellulärer Ebene induziert ein Hitzeschock (HS) bei klinisch relevanten Temperaturen (41,8°C/43°C) unter anderem eine temporäre Defizienz der Homologen Rekombinationsreparatur (HR), einem essentiellen Mechanismus für die fehlerfreie Reparatur von DNA-Doppelstrangbrüchen (DSB). Dies steht im Zusammenhang mit einer hitzeinduzierten proteosomalen Degradierung von BRCA2, einer unerlässlichen Komponente der HR. Trabectedin (Tr) ist eine antiproliferativ wirksame Substanz, die ursprünglich aus dem marinen Tunikat Ecteinascidia turbinata isoliert wurde. Die vielfältigen zytotoxischen Aktivitäten von Tr umfassen neben dem Interferieren mit der aktivierten Transkription und der Modulation der Tumor-Mikroumgebung hauptsächlich die Induktion von DSBs. Seit 2007 wird Tr in der Zweitlinientherapie zur Behandlung refraktärer STS, sowie bei Patienten eingesetzt, bei denen die Erstlinientherapie (Ifosfamid und/oder Doxorubicin) nicht angewendet werden kann. In Anbetracht der hitzeinduzierten Inaktivierung von BRCA2 und den DNA schädigenden Eigenschaften von Tr wurde in dieser Arbeit untersucht, ob und wie die Hyperthermie zu einer Wirkungsverstärkung der zytotoxischen Effekte von Tr beitragen kann. Tr bewirkt in vitro bei Zelllinien unterschiedlicher Sarkomentitäten (U2Os, SW872, SW982) eine dosisabhängige Reduktion des klonogenen Überlebens, das durch einen HS zusätzlich verstärkt wird. Die erhöhte antiproliferative Aktivität von Tr nach einem HS wird als thermale Chemosenitivierung definiert. Zudem konnte durch die Analyse der DNA-Verteilung bei U2Os und SW872 Zellen eine Intensivierung und Verlängerung der Tr-induzierten G2/M-Blockade nachgewiesen werden. Darüber hinaus wurden Zelllinien-spezifische Unterschiede bezüglich einer behandlungsinduzierten Apoptoseinduktion oder Senseszenzantwort identifiziert. SW872 Zellen weisen einen dosis- und temperaturabhängigen Anstieg des Anteiles apoptotischer Zellen auf, der mit einer starken Aktivierung der Effektorcaspasen 3 und 7 einhergeht. Dem entgegen gehen U2Os Zellen in eine ausgeprägte behandlungsinduzierte zelluläre Seneszenz über. Anhand der quantitativen Analyse Tr-induzierter H2AX Foci hat sich ein relevanter Anstieg an DSBs durch eine zusätzliche Hitzeexposition herausgestellt, der eine Beeinträchtigung der BRCA2-vermittelten vollständigen Assemblierung der DNA-Reparaturfoci vermuten lässt. Die Hypothese einer thermalen Chemosensitivierung gegenüber Tr durch eine hitzeinduzierte HR-Defizienz – insbesondere im Rahmen der hitzeinduzierten BRCA2 Degradierung – wurde zudem durch das Ausbleiben der hitzebedingten Verstärkung der Tr-induzierten Zytotoxizität bei BRCA2-defizienten Zellen bekräftigt. Darüber hinaus wurde durch Hochdurchsatzanalysen bestätigt, dass eine hitzevermittelte, erhöhte antiproliferative Aktivität von Tr nach einem Knockdown zahlreicher HR-spezifischer Komponenten ausbleibt. Durch Hochdurchsatzanalysen sowie durch anschließende Validierungsexperimente wurden Proteine identifiziert, die sich als relevant für weitere präklinische und klinische Untersuchungen herausgestellt haben. Die Proteine BRCA1, PARP1 und CHEK1 stellen dabei potentielle molekulare Marker für ein Tumoransprechen auf die Kombinationstherapie von Tr und Hyperthermie dar. Deren Inhibition erwies sich zudem als eine weitere Strategie, um die Effektivität der ursprünglichen Behandlung zusätzlich zu erhöhen. Darüber hinaus wurde die Funktion von FANCD2 als prädiktiver Marker und von ERCC1 als Resistenzmarker für das Therapieansprechen einer alleinigen Tr-Behandlung in vitro bestätigt. Die herausgearbeitete thermale Chemosensitivierung gegenüber Tr mit Hyperthermie durch die induzierte HR-Defizienz mittels passagerer BRCA2 Degradierung (induzierte synthetische Letalität) sowie die Identifizierung weiterer Proteine, deren medikamentöse Inhibition die Effektivität der Kombinationsbehandlung zusätzlich erhöhen könnte, eröffnen neue Möglichkeiten in der Therapie solider Tumoren.

Ziel der Studie war es, die mehrfach wiederholte Anästhesie mit Methadon, Alfaxalon und Isofluran während der Therapie des inoperablen felinen Fibrosarkoms mit Doxorubicin-beladenen thermosensitiven Phosphatidyldiglycerin-Liposomen, die auf dem synthetischen 1,2-Dipalmitoyl-sn-glycero-3-phosphodiglycerol basieren (DPPG2-TSL-DOX), in Kombination mit regionaler Hyperthermie zu evaluieren. Des Weiteren wurde untersucht, ob im Rahmen der regionalen Hyperthermie eine systemische Hyperthermie auftritt. In die prospektive, experimentelle, observative Studie wurden 14 Katzen mit histologisch bestätigtem Fibrosarkom und einer Anästhesierisikoeinstufung in die Klassen 2 und 3 nach der American Society of Anesthesiologists aufgenommen. Neun Katzen beendeten die Studie. Bei fünf Katzen kam es zum Studienabbruch. Die Katzen wurden mit Methadon (Comfortan® Eurovet Animal Health BV., Ae Bladel, Niederlande) in einer Dosierung von 0,2 mg/kg intravenös prämediziert und mit Alfaxalon (Alfaxan®, Jurox (UK), London, Großbritannien) in einer Dosierung von 1,0 bis 4,0 mg/kg intravenös nach Effekt eingeleitet. Die Anästhesieerhaltung erfolgte mittels Inhalationsanästhesie mit Isofluran (IsoFlo®, Abbott Laboratories Ltd, Maidenhead Birkshire, England) in 100 % Sauerstoff. Die Studienteilnehmer wurden in vier Gruppen mit unterschiedlichen Doxorubicindosierungen von 0,1 bis 0,8 mg/kg eingeteilt. Pro Katze wurden sechs Therapiesitzungen im Abstand von zwei Wochen veranschlagt. Der Tumor wurde erhitzt und bei Erreichen der Zieltemperatur erfolgte die intravenöse Verabreichung des DPPG2-TSL-DOX über 15 Minuten sowie eine Fortführung der regionalen Hyperthermie-Behandlung über 60 Minuten. Während der Anästhesien wurden die Tiere kontinuierlich überwacht. Die Anästhesie mit Methadon, Alfaxalon und Isofluran erwies sich als praktikabel, war jedoch von nicht optimalen Begleiterscheinungen gekennzeichnet. In insgesamt 18 Sitzungen trat bei neun Tieren eine Bradykardie auf, die einer Gabe von Glycopyrroniumbromid bedurfte. Bei sechs Tieren in insgesamt neun Sitzungen wurde eine Tachykardie dokumentiert, die bei vier Katzen in insgesamt fünf Sitzungen während der Gabe des DPPG2-TSL-DOX auftrat. Von den tachykarden Katzen erhielt eine Katzen zuvor Glycopyrroniumbromid und vier Katzen Dopamin. Während insgesamt 49 Anästhesien wurde bei 13 Tieren eine Hypotension beobachtet, die zur Stabilisierung des Blutdruckes eine Dopamin-Dauertropfinfusion notwendig machte und in 39 Sitzungen bereits vor der DPPG2-TSL-DOX-Gabe dokumentiert wurde. Eine Hypertension, die in allen drei Fällen zum Zeitpunkt 5 Minuten nach Start der DPPG2-TSL-DOX-Gabe auftrat, wurde bei drei Tieren in insgesamt drei Sitzungen dokumentiert. Alle drei Katzen erhielten zum Zeitpunkt der Hypertension zugleich Dopamin. Bei keiner Katze wurde eine Hypoxämie oder eine Hyperkapnie beobachtet. Bei einer Katze kam es nach Einleitung zu einmaligem Erbrechen. Es verstarben keine Katzen im Verlauf der durchgeführten Anästhesien. Im Rahmen der Therapiesitzungen wurden neben den moderaten Veränderungen der oben genannten Parameter vereinzelt geringfügige Komplikationen dokumentiert. Diese Komplikationen, zu denen vereinzeltes Speicheln auf Methadongabe, eine einmalig auftretende Speichelansammlung in der Trachea, viermaliges Husten und zweimalige Schwellungen im Gesichtsbereich zählten, waren alle vorrübergehend und nicht eindeutig in direkten Zusammenhang mit der Anästhesie oder der DPPG2-TSL-DOX-Gabe zu bringen. Die regionale Hyperthermie hatte keine systemische Hyperthermie zur Folge. Bei allen Katzen wurde eine rektale und oesophageale Hypothermie unter 38,0 °C über den gesamten Anästhesiezeitraum dokumentiert, die trotz aktiver Erwärmung bei allen bis auf eine Katze bis zum Ende der Anästhesie vorhanden war. Des Weiteren wurden keine subjektiven Besonderheiten und Komplikationen im Rahmen der Studie beobachtet, die Nebenwirkungen der Anästhesie, der DPPG2-TSL-DOX-Applikation oder der regionalen Hyperthermie sein könnten. Es traten keine weiteren Nebenwirkungen auf, die auf eine anaphylaktische oder auf eine Hypersensitivitätsreaktion hinwiesen. Für eine bessere Differenzierung und Zuordnung der Auswirkungen von Anästhesie und DPPG2-TSL-DOX in Kombination mit regionaler Hyperthermie wäre die Einführung einer Kontrollgruppe sinnvoll.

Sat, 18 Jul 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18589/ https://edoc.ub.uni-muenchen.de/18589/1/Stoz_Valerie_S.pdf

Sat, 18 Jul 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18535/ https://edoc.ub.uni-muenchen.de/18535/1/Troedson_Eva_Karin_Elisabeth.pdf Troedson, Eva Karin Elisabeth

This episode describes the anthracycline drugs, doxorubicin, daunorubicin and others. It describes the disease we treat with these drugs, the way they are given, and the particular side effects that may occur.

Sat, 12 Jul 2014 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17210/ https://edoc.ub.uni-muenchen.de/17210/1/Zimmermann_Katja.pdf Zimmermann, Katja

Auf DPPG2 basierende thermosensitive Liposomen (TSL) mit Hyperthermie (HT) induzierter zielgerichteter Wirkstofffreisetzung sind eine viel-versprechende Behandlungsstrategie in der Krebstherapie. TSL können als Wirkstoffträgersysteme die Zirkulationszeit und Anreicherung von Wirkstoffen im Zielgewebe erhöhen. Die vielfältigen Krebserkrankungen zeigen unterschiedliches Tumoransprechen auf die routinemäßig eingesetzten Zytostatika. Daher wäre es vorteilhaft, verschiedene Wirkstoffe in TSL einschließen zu können, um Erstlinientherapien weiter zu verbessern. In dieser Arbeit wurden Mitomycin C (Mito) und Gemcitabin (Gem) erstmals in TSL eingeschlossen. Außerdem wurden sie in vitro und in vivo charakterisiert. Die bereits untersuchten TSL(Dox) sollten ihre Vorzüge in einem in dieser Arbeit neuentwickelten orthotopen Blasenkarzinom-Model der Ratte demonstrieren. In Pharmakokinetikstudien wurde die Stabilität der TSL-Formulierungen getestet, die Dosisabhängigkeit untersucht und die Plasmahalbwertszeiten bei wiederholten Injektionen miteinander verglichen. Außerdem wurde eine neue Methode für die Tumorgenerierung und HT-Behandlung in der Rattenblase etabliert. Anschließend wurde die Gewebeverteilung und Tumoranreicherung in der Blase nach Behandlung mit TSL(Dox) +HT untersucht. Die Ergebnisse wurden mit denen der intravesikalen Therapie verglichen. Zusätzlich wurde die Therapieeffizienz von TSL(Gem) im subkutanen Weichteilsarkom untersucht. Die Liposomen wurden durch die Lipidfilmhydratisierungs- und Extrusionsmethode hergestellt und aktiv oder passiv mit Wirkstoff beladen. Die TSL wurden mit Hilfe von dynamischer Lichtstreuung, Dünnschicht-chromatographie, Phosphatbestimmung, Fluoreszenzspektroskopie und HPLC-Analyse charakterisiert. In vivo-Experimente wurden unter Inhalationsnarkose in weiblichen F344 Ratten und männlichen Brown Norway Ratten, durchgeführt. Die HT-Behandlung wurde durch Erwärmung mit Licht oder Wasserbad im Weichteilsarkom-Modell oder einer Blasenspülung mit warmen Wasser im Blasenkarzinom-Modell durchgeführt. TSL(Mito) wiesen eine niedrige Einschlusseffizienz auf und waren in vitro und in vivo sehr instabil. TSL(Gem) und TSL(Dox) hingegen zeigten bei Körpertemperatur eine lange Zirkulationszeit nach intravenöser (i.v.) Verabreichung. TSL(Dox) zeigten bei höherer Verabreichungsdosis eine verlängerte Zirkulationszeit. Wiederholte Injektionen mit TSL(Dox) nach 7 oder 14 Tagen, beeinflussten die Pharmakokinetik des Wirkstoffes nicht. Durch chemische Vorbehandlung der Blase und anschließende Tumorzell-instillation wurde Tumorwachstum in der Blase erzeugt, das nach spätestens 5 Tagen zystoskopisch erkennbar war. Mit kontinuierlicher Spülung mit warmer Flüssigkeit konnte die Blase problemlos für die Behandlungsdauer von 1 h auf 41 °C erwärmt werden. Das Vorhandensein eines Tumors reduzierte die Dox-Aufnahme in die Blasenwand. Bei intravesikaler Therapie mit nicht liposomalem Dox wurden im Urothel bzw. der Tunica muscularis nur 78% bzw. 45% der Konzentration erreicht, die bei systemischen Injektion mit TSL(Dox) +HT erreicht wurde. Die Therapie des Weichteilsarkoms mit Gem zeigte den Vorteil des liposomalen Einschlusses von Gem im Vergleich zum freien Wirkstoff. TSL(Gem) -HT zeigte eine geringfügigere Tumorwachstumsverzögerung verglichen mit freiem Gem ±HT. Die HT induzierte Wirkstofffreisetzung zeigte eine signifikante stärkere Inhibierung des Tumorwachstums verglichen mit allen anderen Gruppen. Die Resultate zeigen, dass nicht alle Wirkstoffe für den Einschluss in auf DPPG2 basierende Liposomen geeignet sind. Die Pharmakokinetik wird bei wiederholter Applikation nicht durch verstärkten Liposomenabbau beeinflusst. TSL und HT zeigten Vorteile in der Anreicherung und Therapie in verschiedenen Tumormodellen. TSL in Kombination mit HT sind eine wertvolle Errungenschaft für die Krebstherapie und sollten weiter untersucht werden.

Sarkome stellen eine heterogene Gruppe von mesenchymalen Tumoren mit einem teilweise aggressiven klinischen Verlauf dar. Die biomedizinische Forschung untersucht molekulare Mechanismen, um durch eine gezielte Pharmaka-Modulierung die Effizienz klassischer Behandlungsmethoden zu steigern. Ein vielversprechendes therapeutisches Verfahren basiert auf der Anwendung der Hyperthermie in Kombination mit einer Standardchemotherapie. Die biologischen Auswirkungen der Hyperthermie auf intrazelluläre Prozesse, wie z.B. Signaltransduktionskaskaden, Reparaturmechanismen und Apoptosewege sind bislang nur teilweise erforscht. In der Arbeit wurde die Auswirkung eines Hitzeschocks auf den anti-apoptotischen Akt-mTOR-Signaltransduktionsweg und dessen Bedeutung für die Vitalität der mit Hitze- oder Thermo-Chemotherapie behandelten Krebszellen in vitro untersucht. Anhand der in unterschiedlichen Sarkomzelllinien durchgeführten Analysen konnte festgestellt werden, dass eine Hitzeexposition bei einer klinisch relevanten Temperatur von 41,8°C eine starke Phosphorylierung der Kinasen Akt, mTOR und p70/p85 S6K induziert. Die zeitgleich beobachtete Erhöhung der HSP70-Expression unter einem Hitzeschock deutet auf eine adäquate Antwort der Zellen auf Hitzeschock hin. Die Aktivierung des Akt-mTOR-Signalweges sowie die Induktion von HSP70 wirken anti-apoptotisch. Eine Unterdrückung von PTEN und die resultierende Hyperaktivierung von Akt führten zu einer gesteigerten Proliferation der Zellen. Durch die Hyperaktivierung von Akt konnte die Vitatlität und Koloniebildungsfähigkeit der Zellen nach einem Hitzeschock verbessert werden, was durch Perifosin wiederum unterdrückt werden konnte. Die Anwendung des Akt-Inhibitors Perifosin hat einen stark reduzierenden Effekt auf die konstitutive und Hitzeschock-bedingte Phosphorylierung der Akt-Kinase und ihrer downstream targets. So vermindert Perifosin die Vitalität und das klonogene Überleben von Sarkomzellen, die einem Hitzeschock ausgesetzt wurden. Eine Analyse hinsichtlich des Akt-mTOR-Signalweges in vitro zeigt, dass auch Doxorubicin bei 37°C die Aktivierung der Signalkaskade auslöst. Zusätzlich wird durch Doxorubicin die PARP-Expression verstärkt. Die Kombinationsbehandlung von Sarkomzellen mit Doxorubicin und Perifosin zeigt einen reduzierenden Effekt auf die Akt-Phosphorylierung, sowie die Induktion der PARP-Expression und sensitiviert die Sarkomzellen gegenüber einem Hitzeschock. Darüber hinaus konnte Perifosin die relative Resistenz den Osteosarkom MG63-Zellen und den Fibrosarkom HT1080-Zellen gegenüber Doxorubicin verringern. In Akt-KD-Experimenten konnte dabei gezeigt werden, dass der Effekt von Perifosin spezifisch der Akt-Inhibition zugeschrieben werden kann. Sowohl ein Akt-KD als auch Perifosin führt zu einer Unterdrückung der Phosphorylierung von mTOR und p70/p85 S6K, zu einer Verminderung der Hitze-bedingten HSP70-Induktion und zur Induktion der Apoptose. Die Ergebnisse dieser Arbeit zeigen, dass Akt eine wichtige Rolle in dem intrazellulären Schutzmechanismus und Überleben der dem Hitzeschock ausgesetzten Zellen spielt. Sie deuten auf eine wichtige Rolle des Akt-mTOR-Signalweges bezüglich der Überlebensfähigkeit der Zellen während eines Hitzeschocks hin.

Weichteilsarkome (STS) sind seltene maligne Neoplasien, die von bindegewebigen Strukturen wie Fett-, Muskel- oder Stützgewebe ausgehen und im gesamten Körper auftreten können. Goldstandard der Therapie ist die Resektion aller Manifestationen unter Mitnahme ausreichender Sicherheitsabstände. Da dies jedoch nicht in allen Patienten möglich ist, wird versucht, durch Verabreichung zytostatischer Substanzen eine Tumormassenreduktion zur erreichen. Dies gelingt mit den vorhandenen Chemotherapeutika mit erwiesener Wirksamkeit, insbesondere Doxorubicin, jedoch nur in etwa einem Drittel aller Patienten. Es konnte gezeigt werden, dass die Anwendung einer regionalen Hyperthermie (RHT) das Ansprechen der Patienten verbessert. Noch anspruchsvoller ist die Therapie von Patienten mit bereits metastasierter, rezidivierender oder Doxorubicin-refraktärer Erkrankung. Hier ist bislang keine Standardtherapie definiert. Die vorliegende Arbeit evaluiert eine in dieser Situation angewendete Polychemotherapie, bestehend aus Ifosfamid, Carboplatin und Etoposid (ICE) und appliziert in Kombination mit RHT, hinsichtlich ihrer Wirksamkeit und Verträglichkeit. Zudem wurde die Funktion natürlicher Killerzellen (NK-Zellen) als an der Kontrolle von Neoplasien beteiligte Effektoren des Immunsystems bei Patienten mit STS untersucht. Es konnte gezeigt werden, dass ICE + RHT eine wirksame Therapieoption für Patienten mit Anthrazyklin-refraktärem STS darstellt, und zwar sowohl für Patienten mit als auch ohne Fernmetastasen. Remissionen waren in 13% der Patienten nachweisbar, überwiegend konnte eine Krankheitsstabilisierung erreicht werden. Die Therapie ist jedoch assoziiert mit einer höhergradigen hämatologischen Toxizität und febrilen Komplikationen in einem signifikanten Anteil der Patienten, so dass ICE + RHT nur ausgewählten Patienten in gutem Allgemeinzustand verabreicht werden sollte. Die lytische Funktion der NK-Zellen war noch vor Beginn einer Therapie bei Patienten mit Erstdiagnose eines STS sowie bei Patienten mit Anthrazyklin- refraktärem STS signifikant reduziert im Vergleich zu gesunden Probanden. Während der Therapie mit ICE + RHT zeigte sich keine Zunahme dieser Funktion. Durch Inkubation der Zellen mit Interleukin 2 und TKD, einem Hitzeschockprotein- Derivat mit NK-stimulierenden Eigenschaften, konnte die Funktion in vitro wiederhergestellt werden. Die Augmentation der NK-Zell-Funktion könnte in Zukunft von therapeutischem Nutzen für Patienten mit STS sein.

Das maligne Lymphom ist die häufigste hämatopoetische Neoplasie des Hundes. Die chemotherapeutische Behandlung mit Doxorubicin-haltigen Protokollen wird als die Therapie der Wahl angesehen. Dem Autor ist kein Dosis-intensivierendes simultanes Chemotherapie-Protokoll zur Behandlung des kaninen Lymphoms bekannt. Die Hypothese dieser Studie war, dass die Behandlung mit einem 13-wöchigen Dosis-intensivierenden simultanen Chemotherapie (DISC)-Protokoll zu weniger Nebenwirkungen und vergleichbaren oder sogar besseren Remissionsraten und medianen Remissionszeiten führt. Auftretende Nebenwirkungen sowie Remissionsraten und –zeiten wurden protokolliert. Es wurden prospektiv 21 Hunde mit dem Studienprotokoll behandelt. Die Diagnose ‚malignes Lymphom‘ wurde durch eine zytologische oder histologische Untersuchung gestellt. Das DISC-Protokoll ist ein 13-wöchiges Chemotherapie-Protokoll ohne Erhaltungsphase. An Tag 1 wurde L-Asparaginase (400 IU/kg SC) verabreicht. Danach folgte die wöchentliche simultane Gabe von Vincristin (0,7 mg/m² IV = 100 %), Cyclophosphamid (200 mg/m² IV = 100 %) und Doxorubicin (30 mg/m² IV = 100 %) mit einer initialen Dosisstufe von 33 %. Die jeweiligen Dosisstufen wurden zweimalig verabreicht und dann um 5-7 % bis zu einer maximalen Dosisstufe von 60 % erhöht, wenn keine oder nur Grad-I-Toxizitäten auftraten. Zusätzlich erhielten die Hunde therapiebegleitend für drei aufeinanderfolgende Tage 2 mg/kg Prednisolon und 0,5 mg/kg Furosemid PO. Bei zwei Hunden zeigten sich Grad-IV-Toxizitäten auf (eine asymptomatische Neutropenie bzw. eine Sepsis). Des Weiteren wurden zwei Grad-III-Thrombozytopenien und eine Grad-III-Neutropenie beschrieben. Weitere Nebenwirkungen waren selten und nur geringgradig. Der septische Patient wurde für 48 Stunden hospitalisiert und konnte nach dieser Zeit bei gutem Allgemeinbefinden entlassen werden. Im Verlauf der Studie verstarb keines der Tiere aufgrund von Nebenwirkungen oder wurde deshalb euthanasiert. Es trat auch bei keinem der Hunde eine sterile hämorrhagische Zystitis auf, obwohl alle wöchentlich mit Cyclophosphamid therapiert wurden. Siebzehn Hunde erreichten eine komplette Remission (80,9 %), ein weiterer eine partielle Remission (4,8 %), zwei erfuhren eine stabile Erkrankung (9,5 %) und ein Hund zeigte ein Fortschreiten der Erkrankung (4,8 %). Die mediane Remissionszeit für Hunde in kompletter Remission betrug 294 Tage. Im Vergleich zu anderen konventionellen Kombinations-Protokollen sind das Nebenwirkungsspektrum sowie Remissionsraten und –zeiten vergleichbar bis sogar verbessert. Die inter-individuelle Dosistoleranz innerhalb des Protokolls war sehr weit gefächert. Zwei Hunde konnten optimal bis zur Dosisstufe von 60 % eskaliert werden, weitere fünf konnten auf Dosisstufe 55 % therapiert werden, jedoch konnte bei drei Hunden die Dosis nicht über 33 % hinaus gesteigert werden. Das DISC-Protokoll wurde im Allgemeinen sehr gut toleriert und Remissionsraten sowie –zeiten waren mit konventionellen Kombinations-Protokollen vergleichbar oder sogar verbessert. Zusammenfassend ist zu sagen, dass alle Ziele der Studie erfüllt wurden. Des Weiteren wird momentan das Nachfolger-DISC-Protokoll durchgeführt, bei dem wöchentlich eine Dosissteigerung vorgenommen wird, um einen potentiellen Vorteil dieser individuellen Dosissteigerung bei der Therapie des kaninen Lymphoms zu evaluieren.

Der Naturstoff Betulinsäure (BA) induziert effektiv Apoptose in Tumorzellen. Vorarbeiten der Arbeitsgruppe zeigten, dass BA auf primären Leukämiezellen besser Apoptose in vitro induziert als viele der heute verwendeten Zytostatika. Zelltod wird dabei direkt über Aktivierung des intrinsischen Apoptosesignalwegs am Mitochondrium ausgelöst. Aufbauend auf diesen Daten war es Ziel dieser Dissertation, BA in die Kombinationsabfolge der Polychemotherapie der Leukämie einzuordnen. Zunächst wurde untersucht, mit welchen Zytostatika der heutigen Leukämietherapie Betulinsäure kooperiert, so dass der gemeinsame Einsatz beider Substanzen synergistische Apoptose auslöst. Dabei stellte sich heraus, dass Betulinsäure mit den drei Medikamenten Asparaginase, Doxorubicin und Vincristin kooperiert, sowohl auf sensitiven Tumorzelllinien, auf Zytostatika-resistenten Zelllinien als auch auf primären Zellen von Kindern mit akuter Leukämie. Im Hauptteil der Arbeit wurde untersucht, welche intrazellulären Signalmechanismen für die effektive Apoptoseinduktion von BA mit Asparaginase, Doxorubicin oder Vincristin verantwortlich sind. Dabei erwiesen sich für alle drei untersuchten Zytostatika die Signalmechanismen als identisch. Mittels des Einsatzes von transgenen Tumorzellinien, der Überexpression rekombinanter Proteine sowie des Knockdowns endogener Proteine über RNA-Interferenz konnte gezeigt werden, dass folgende Signalmoleküle die synergistische Apoptoseinduktion vermitteln: der Transkriptionsfaktor p53; das pro-apoptotische BCL-2 Familienmitglied NOXA, dessen Expression über p53 reguliert wurde; die mitochondriale Aktivierung mit Freisetzung von z.B. Cytochrom-C, die durch Mitglieder der BCL-2 Familie reguliert wurde; hierbei ermöglichte die p53-abhängige Regulation von NOXA eine Verschiebung des Gleichgewichts in Richtung zur Apoptose; Caspasen (Casp-3 und -9). Um die intrazelluläre Signaltransduktion auch an Patienten-abgeleiteten Zellen untersuchen zu können, wurde eine neue Technik etabliert: Kindliche ALL-Zellen wurden in immuninkompetenten Mäusen vermehrt und mittels eines optimierten Protokolls der Elektroporation mit small interfering RNA transfiziert. Auch hier zeigte sich eine Abhängigkeit der synergistischen Apoptoseinduktion von p53 und NOXA. Die dargelegten Untersuchungen legen nahe, BA in zukünftigen prä-klinischen und klinischen Studien der Leukämie in der Nähe von Doxorubicin, Asparaginase oder Vincristin einzusetzen, um von der günstigen p53-abhängigen Aktivierung von NOXA durch Zytostatika-Kombination zu profitieren.

Monomeric actin controls the activity of the transcription factor Serum Response Factor (SRF) via its coactivator MAL/MRTF-A. Upon signal induction, MAL is released from actin, binds SRF and activates target gene expression. In order to characterise the physiological role of this signalling pathway, I screened on a genome wide basis for target genes by transcriptome analysis. A combination of actin binding drugs (Cytochalasin D and Latrunculin B), targeting monomeric actin, was used to specifically and differentially interfere with the complex between MAL and actin. 210 genes primarily controlled by monomeric actin were identified in mouse fibroblasts. Among them more than 30% have been already found in screens for SRF target genes, supporting the validity of the screening approach. As expected, a lot of genes were involved in cytoskeleton organization. However, genes having anti-proliferative or pro-apoptotic features were identified surprisingly to the same extent. Consistently, I could demonstrate an antiproliferative function of MAL. More specifically, several genes interfering with the MAPK pathway were identified. One of them was Mig6/Errfi1, a negative regulator of EGF receptors. Mig6 induction by LPA or FCS revealed to be dependent on MAL, monomeric actin and the small GTPases Rho. Activated forms of MAL or SRF were sufficient to induce Mig6 expression. Subsequently, a Mig6 promoter element was found to be necessary to mediate MAL/SRF induction. Moreover, induction of Mig6 through the Actin-MAL pathway led to the downregulation of the mitogenic EGFR-MAP kinase cascade. For the first time a transcriptional link between G-actin levels sensed by MAL and the regulation of EGFR signalling was established. Furthermore, after having demonstrated that MAL induces apoptosis, I focused on the characterisation of two proapototic targets identified in the screen: Bok and Noxa. Bok and Noxa were induced by activators of the Rho-Actin-Mal-Srf pathway on a MAL dependent manner. The study of the Bok promoter revealed the existence of a response element that was necessary for the induction by MAL-SRF. Interestingly, apoptotic inducers like staurosporine, TNFα, or the DNA damaging agent Doxorubicin triggered MAL-SRF mediated transcription. As SRF controls the expression of the anti-apoptotic genes Bcl2 and Mcl1, the results from this work places thus SRF as a key transcription factor controlling the balance between pro and anti apoptotic genes in response to external cues.

Purpose: Previous phase II studies have indicated a greatly reduced hematotoxicity of docetaxel-based regimens administered on weekly schedules. The present trial was initiated to compare the toxicity and efficacy of weekly docetaxel versus its standard 3-weekly application in combination with doxorubicin. Methods: Patients previously untreated with chemotherapy for metastatic disease were recruited. Inclusion criteria were age = grade 3 was observed in the standard arm of the D4 study compared to the weekly schedule (per-patient analysis: 61.9% q3w vs. 65.1% q1w; p > 0.05). Grade 3 and grade 4 fever, diarrhea, and infections occurred more frequently in the standard arm, whereas neurotoxicity and skin/nail disorders were observed more frequently in the weekly arm. Except for fever, none of these differences reached a level of significance. Dose delays, dose reductions, and the rate of omitted doses were increased in the weekly arm. The overall response rate was 44.2% in the weekly arm compared to 52.4% in the standard arm (p = 0.52). Time to progression was 6.2 (q1w) versus 10.3 (q3w) months (p = 0.36), and overall survival was 20.5 (q1w) versus 28.7 (q3w) months (p = 0.98). Conclusion: The present data support the feasibility of both weekly and 3-weekly application of docetaxel in combination with doxorubicin. Nevertheless, given that leukopenia was similar in both arms and the efficacy parameters were at least numerically inferior with the weekly schedule, standard 3-weekly application seems to be preferable for patients requiring combination chemotherapy. Copyright (C) 2011 S. Karger AG, Basel

Thu, 3 Dec 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/10883/ https://edoc.ub.uni-muenchen.de/10883/1/Armann_Jakob.pdf Armann, Jakob

Oncology, December 13th, 2007 Reporting from: San Antonio Breast Cancer Symposium, 13-16 December, 2007 Early Breast Cancer: Survival Benefit For Adjuvant Docetaxel/Cyclophosphamide STEPHEN JONES, US Oncology Research, Houston REFERENCE: ABSTRACT 12 Long term data from an early breast cancer trial involving cyclophosphamide combined with docetaxel or doxorubicin have shown a survival advantage for the taxane. As Stephen Jones of US Oncology Research explained to Derek Thorne, this advantage was also seen in patients over 65.

Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8196/1/liposomal_doxorubicin_in_the_treatment_of_advanced_aids-related_kaposi_sarcoma_8196.pdf Goebel, Frank-Detlef; Trübenbach, K.; Rolinski, B.; Kronawitter, Ursula; Bogner, Johannes R. ddc:61

Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8197/1/liposomal_doxorubicin_in_the_treatment_of_aids-associated_karposis_sarcoma_8197.pdf Bogner, Johannes R.; Hofschneider, P. H.; Gillitzer, R.; Goebel, Frank-Detlef; Eisenburg, B.; Zietz, C.; Stürzl, M. ddc:610, M