Podcasts about intraperitoneal

During this episode of Making the Rounds, we'll discuss an innovative treatment in abdominal cancers – hyperthermic intraperitoneal chemotherapy, commonly known as HIPEC surgery.   Joining me today on Making the Rounds is Dr. Carrie Luu, a surgical oncologist specializing in abdominal cancers at Banner – University Medicine Tucson and the University of Arizona Cancer Center, and clinical assistant professor with the University of Arizona College of Medicine – Tucson, Department of Surgery in the Division of Surgical Oncology. To learn more about this topic or other oncology related services provided at the University of Arizona Cancer Center, please visit cancercenter.arizona.edu.

In this episode of SurgOnc Today®, Samantha Ruff, MD, Rupen Shah, MD, Mustafa Raoof, MD, and Danielle DePeralta, MD, discuss the role of pressurized intraperitoneal aerosolized chemotherapy (PIPAC) and its emerging role in the management of peritoneal surface malignancies. We review the existing literature for this treatment modality and the recently published multi-center phase I trial performed in the United States. 

Rick Greene, MD discusses with Edward A. Levine, MD, long-term survival in patients with malignant peritoneal mesothelioma undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Dr. Levine is the senior author of, “Long-Term Survival in Patients Treated with Cytoreduction and Heated Intraperitoneal Chemotherapy for Peritoneal Mesothelioma at a Single High-Volume Center.” Dr. Levine is Professor, Surgical Sciences - Oncology, Chief of Surgical Oncology at Atrium Wake Forest Health, and Section Editor of the Peritoneal Surface Malignancies section of the Annals of Surgical Oncology.  https://link.springer.com/article/10.1245/s10434-022-13061-3

This week we sit down with Oliver Eng, MD, FACS, FSSO to discuss heated intraperitoneal chemotherapy (HIPEC). Dr. Eng is a surgical oncologist and an Associate Professor in the Division of Surgical Oncology at the University of California, Irvine, where he is also Associate Director of the Peritoneal Surface Malignancy Program as well as the Complex General Surgical Oncology Fellowship. He is a double board-certified surgeon and surgical oncologist who specializes in the treatment of cancers in the abdomen, particularly cancers that have spread to the peritoneum, the membrane that lines the abdominal cavity. He specializes in complex cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC). Dr. Eng has co-authored numerous peer-reviewed manuscripts in journals including Cancer Discovery, Journal of Clinical Oncology, Cancer, and British Journal of Cancer. He has received numerous teaching and research awards and was most recently a recipient of The Lynx Group's 40 Under 40 in Cancer Award, which recognizes the contributions being made across the field of cancer by emerging leaders nationally.

“Before you even get started, you have to do your checks. Just like you do with a regular systemic infusion. You're going to be doing your physical assessment prior to starting your patient, looking at your orders to make sure everything looks right, looking at the lab work,” ONS member Emoke Karonis, MSN, RN, CRNI, clinical nurse specialist fellow at Memorial Sloan Kettering Cancer Center in New York, NY, said. “You have to be absolutely sure that day that patient is presenting to you in your suite, you're definitely giving what is expected for that day.” Karonis was speaking to Jaime Weimer, MSN, RN, AGCNS-BC, AOCNS®, oncology clinical specialist at ONS, about oncology nursing considerations for intraperitoneal chemotherapy administration. 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) by listening to the full recording and completing an evaluation at myoutcomes.ons.org by March 24, 2025. 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 related to intraperitoneal therapy for cancer. Episode Notes: Complete this evaluation to earn free NCPD. Oncology Nursing Podcast Episode 162: What Nurses Need to Know About Central Lines and Ports ONS Voice articles: Nursing Considerations for Ovarian Cancer Survivorship Care Ovarian Cancer: Prevention, Screening, Treatment, and Survivorship Recommendations ONS book: Access Device Standards of Practice for Oncology Nursing American Cancer Society: Chemotherapy for ovarian cancer American Society of Clinical Oncology guideline: Treatment of Metastatic Colorectal Cancer Cancercare.org treatment update: Ovarian cancer Centers for Disease Control and Prevention: Information on ovarian cancer National Institute of Diabetes and Digestive and Kidney Diseases: Information on peritoneal dialysis European Society for Medical Oncology Infusion Nurses Society National Comprehensive Cancer Network To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From Today's Episode “Intraperitoneal (IP) therapy is basically the administration of an agent into that space where the abdominal organs float around via an implanted port or one of those direct intraabdominal catheters. . . Patients with cancer that have metastasized to the peritoneum, who have either had a debulking surgery and have very little disease left inside or small tumors to begin with, they can be considered for IP therapy.” Timestamp (TS) 02:02 “Hyperthermic IP chemotherapy is done in the operating room right after the surgeon has done all of their tumor removal. It is hyperthermic, meaning this stuff is hot, and it gets administered via a special circulating machine that heats up the chemotherapy and circulates it throughout the abdomen. . . . They are circulated for about 90 minutes–2 hours if they are at risk of overheating.” TS 07:39 “In the infusion suite, before you even get started, you have to do your checks. Just like you do with a regular systemic infusion. You're going to be doing your physical assessment prior to starting your patient, looking at your orders to make sure everything looks right, looking at the lab work. . . If it's the first time you're seeing the patient, you want to check for catheter confirmation. It's not going to be in a vessel, it's going to be in the abdomen. You want to make sure that, especially if the person has more than one access device, you are looking for the correct confirmation.” TS 14:00 “It is necessary to repeat yourself because we're giving patients so much information at the presurgical visit, while they're going into the operating room, when they come out of the operating room, on their discharge, and then they're going to go into the clinic for their post-op visit. There's so much being thrown at these folks all the time that you do need to constantly reteach the same thing and to always be very neutral and accepting of that—that people might not retain everything you tell them the first time.” TS 22:00 “You can't emphasize enough that if there's one point where you need to slow down, take a breath, is during that independent double check. You have to be absolutely sure that day that patient is presenting to you in your suite, you're definitely giving what is expected for that day. If they're coming in multiple days, they could have a regimen that changes from day to day. . . . It's so easy to get confused, and it's very important to go back and see what has happened before that patient showed up at your suite, what's expected to happen that day, and what's going to happen the following day.” TS 31:16

This month on Episode 45 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the February 3rd and February 17th issues of Circulation Research. This episode also features an interview with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.   Article highlights:   Pi, et al. Metabolomic Signatures in PAH   Carnevale, et al. Thrombosis TLR4-Mediated in SARS-CoV-2 Infection   Cai, et al. Macrophage ADAR1 in AAA   Koide, et al. sEVs Accelerate Vascular Calcification in CKD   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting the articles from our February 3rd and 17th issues of Circulation Research. I'm also going to have a chat with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study, Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. But before I get to the interviews, here are a few article highlights.   Cindy St. Hilaire:        The first article I want to highlight comes from the laboratory of Dr Peter Leary at the University of Washington, and the title is Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes. Pulmonary Arterial Hypertension or PAH is a rare but life-threatening disease in which progressive thickening of the walls of the lung's blood vessels causes increased blood pressure and that increased blood pressure ultimately damages the heart's right ventricle.   Interestingly, progression to heart failure varies considerably among patients, but the reasons why there is variability are not well understood. To find out, this group turned their attention to patient metabolomes, which differ significantly from those of healthy people and thus may also change with severity. Blood samples from 117 PAH patients were analyzed for more than a thousand metabolites by mass spectrometry and the patient's progress was followed for the next three years. 22 patients died within a three-year period and 27 developed significant right ventricle dilation. Other measures of severity included pulmonary vascular resistance, exercise capacity and levels of BNP, which is a metric of heart health. Two metabolic pathways, those relating to polyamine and histidine metabolism, were found to be linked with all measures of severity suggesting a key role for them in disease pathology. While determining how these pathways influence disease as a subject for further study, the current findings may nevertheless lead to new prognostic indicators to inform patient care.   Cindy St. Hilaire:        The next article I want to discuss is coming from our February 3rd issue of Circulation Research and this is coming from the laboratory of Dr Francisco Violi at the University of Rome and the title is Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection. Thrombosis can be a complication of COVID-19 and it is associated with poor outcomes, including death. However, the exact mechanism by which the virus activates platelets, which are the cells that drive thrombosis, is not clear. For one thing, platelets do not appear to express the receptor for SARS-CoV-2. They do however, express the TLR4 receptor and that's a receptor that mediates entry of other viruses as part of the immune response. And TLR4 is ramped up in COVID-19 patient platelets. This group now confirms that, indeed, SARS-CoV-2 interacts with TLR4, which in turn triggers thrombosis.   The team analyzed platelets from 25 patients and 10 healthy controls and they found that the platelet activation and thrombic activity were both boosted in the patient samples and could not be blocked using a TLR4 inhibitor. Additionally, immunoprecipitation and immunofluorescent experiments further revealed colocalization between the virus protein and the TLR4 receptor on patient platelets. The team went on to show that the signaling pathway involved reactive oxygen species producing factors p47phox and Nox2, and that inhibition of phox 47, like that of the TLR4 receptor itsel,f could prevent platelet activation. As such, this study suggests that inhibiting either of these proteins may form the basis of an antithrombotic treatment for COVID-19.   Cindy St. Hilaire:        The third article I want to highlight is coming from the lab of Shi-You Chen at University of Missouri and the title of this article is ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm. Macrophage activation plays a critical role in abdominal aortic aneurysm development, or AAA development. Inflammation is a component of this pathology; however, the mechanisms controlling macrophage activation and vascular inflammation in AAA are largely unknown. The ADAR1 enzyme catalyzes the conversion of adenosine to inosine in RNA molecules and thus this conversion can serve as a rheostat to regulate RNA structure or the gene coding sequence of proteins. Several studies have explored the role of ADAR1 in inflammation, but its precise contribution is not fully understood, so the objective of this group was to study the role of ADAR1 in macrophage activation and AAA formation.   Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development and dissection and angiotensin II infusion of ApoE knockout mice combined with a macrophage specific knockout of ADAR1 was used to study the role of ADAR1 macrophage specific contributions to AAA formation and dissection. Allograft transplantation of wild type abdominal aortas to ADAR1 haploinsufficient recipient mice significantly attenuated AAA formation. ADAR1 deficiency in hematopoietic stem cells also decreased the prevalence and the severity of AAA and it also inhibited macrophage infiltration into the aortic wall. ADAR1 deletion blocked the classic macrophage activation pathway. It diminished NF-κB signaling and it enhanced the expression of a number of anti-inflammatory microRNAs. Reconstitution of ADAR1 deficient but not wild type human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. Together these results suggest that macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism of editing the microRNAs that target NF-κB signaling, which ultimately promotes vascular inflammation in AAA.     Cindy St. Hilaire:        The last article I want to highlight is also from our February 17th issue of Circulation Research and it is coming from the lab of Shintaro Mandai at Tokyo Medical and Dental University and the title of the article is Circulating Extracellular Vesicle Propagated MicroRNA signatures as a Vascular Calcification Factor in Chronic Kidney Disease. Chronic Kidney Disease or CKD accelerates vascular calcification in part by promoting the phenotypic switching of vascular smooth muscle cells to osteoblast like cells. This study investigated the role of circulating small extracellular vesicles or SUVs from the kidneys in promoting this osteogenic switch. CKD was induced in rats and in mice by an adenine induced tubular interstitial fibrosis and serum from these animals induced calcification in in vitro cultures of A-10 embryonic rat smooth muscle cells. Intraperitoneal administration of a compound that prevents SEV biosynthesis and release inhibited thoracic aortic calcification in CKD mice under a high phosphorus diet. In Chronic Kidney Disease, the microRNA transcriptome of SUVs revealed a depletion of four microRNAs and the expression of the microRNAs inversely correlated with kidney function in CKD patients.   In vitro studies found that transected microRNA mimics prevented smooth muscle cell calcification in vitro. In silico analyses revealed that VEGF-A was a convergent target of all four microRNAs and leveraging this, the group used in vitro and in vivo models of calcification to show the inhibition of the VEGF-A, VEGFR-2 signaling pathway mitigated calcification. So in addition to identifying a new potential therapeutic target, these SUV propagated microRNAs are a potential biomarker that can be used for screening patients to determine the severity of CKD and possibly even vascular calcification.   Cindy St. Hilaire:        Today I have with me Dr Hind Lal who's an associate professor of medicine at the University of Alabama Birmingham and his post-doctoral fellow and the lead author of the study Dr Tousif Sultan. And their manuscript is titled Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. And this article is in our February 3rd issue of Circulation Research. So thank you both so much for joining me today.   Tousif Sultan:              Thank you.   Hind Lal:                     Thank you for taking time.   Cindy St. Hilaire:        So ponatinib, it's a tyrosine kinase inhibitor and from my understanding it's the only treatment option for a specific group of patients who have chronic myelogenous leukemia and they have to harbor a specific mutation. And while this drug helps to keep these patients alive essentially, it's extremely cardiotoxic. So cardiotoxicity is somewhat of a new field. So Dr Lal, I was wondering how did you get into this line of research?    Hind Lal:                    So I was fortunate enough to be in the lab of Dr Tom Force and he was kind of father of this new area, now is very developed, it's called cardio-oncology. On those days there were basically everything started in cardio-oncology. So I just recall the first tyrosine kinase approved by FDA was in 2000 and that was... Imagine and our paper came in Nature Medicine 2005 and discovering there is... so to elaborate it a little bit, the cancer therapy broadly divided in two parts. One is called non-targeted therapy like chemotherapy, radiations, et cetera, and then there are cytotoxic drugs. So those cytotoxic drugs because they do not have any targeted name on it so they are, cardiotoxic are toxic to any organ was very obvious and understanding. When these targeted therapy came, which is mainly kinase inhibitor are monoclonal antibodies. So these are targeted to a specific pathway that is activated only in the cancer cells but not in any other cells in the body so they were proposed as like magic bullets that can take off the cancer without any cardiotoxity or minimal side effects. But even in the early phase like 2005 to 2010, these came out, these so-called targeted, they are not very targeted and they are not also the magic bullets and they have serious cardiotoxicity.   Cindy St. Hilaire:        And so what's the mechanism of action of ponatinib in the leukemia and how does that intersect with the cardiovascular system?   Hind Lal:                     Yeah, so this is very good question I must say. So what we believe at this point because, so leukemia if you know is driven by the famous Philadelphia chromosome, which is a translicational gene, one part of human chromosome nine and one part of human chromosome 22 and they translocate make a new gene which is BCR-ABL gene. And because it was discovered in Philadelphia UPENN, is named that Philadelphia chromosome, which is very established mechanism, that's how CML is driven. But what we have discovered that the cardiotoxicity driven by totally, totally different from the ponatinib is one of the inflammatory So it's kind of goodening. So this question is so good. One kind of toxicity is called on-target, when toxicity is mediated by the same mechanism, what is the mechanism of the drug to cure the cancer? So in that case your absolute is minimal because if you manipulate that, the drug's ability to cure the cancer will be affected but if the toxicity and the efficacy is driven by two different mechanism, then as in case of ponatinib seems like it's NLRP3 and inflammasome related mechanism. So this can be managed by manipulating this pathway without hampering the drug efficacy on the cancer.   Cindy St. Hilaire:        So what exactly is cardiotoxicity and how does it present itself in these patients?   Hind Lal:                     So these drugs like ponatinib, they call broader CVD effects. So it's not just cardiac, so they also in hypertensives and atherosclerosis and thrombosis, those kind of thing. But our lab is primarily focused on the heart. So that's why in this paper we have given impresses on the heart. So what we believe at this point that ponatinib lead to this proinflammatory pathway described in this paper, which is just 108A9-NLRP3-IL-1β and this inflammatory pathway lead to a cytokine storm very much like in the COVID-19 and these cytokine storms lead to excessive myocarditis and then finally cardiac dysfunction.   Cindy St. Hilaire:        Is the cytokine storm just local in the cardiac tissue or is it also systemic in the patients? Is cardiotoxicity localized only or is it a more systemic problem?   Tousif Sultan:              I would like to add in this paper we have included that we look this cytokine things and explain blood circulation, bone marrow. So the effect is everywhere, it's not local. So we didn't check other organs, maybe other organs also being affected with the ponatinib treatment.   Cindy St. Hilaire:        And what's the initial phenotype of a patient has when they start to get cardiotoxicity, what's kind of like a telltale symptom?   Hind Lal:                     So good thing that in recent years cardio-oncology developed. So initially the patient that were going for cancer treatment, they were not monitored very closely. So they only end up in cardiology clinic when they are having some cardiac events already. So thanks to the lot of development and growth in the cardio-oncology field, now most patients who going for a long-term cancer treatment, they are closely monitored by cardiology clinics.   Cindy St. Hilaire:        Got it. So they can often catch it before a symptom or an event. That's wonderful.   Hind Lal:                     Yeah, so there's a lot of development in monitoring.   Cindy St. Hilaire:        Wonderful. So you were really interested in figuring out why ponatinib induces cardiotoxicity and you mentioned that really up until now it's been very difficult to study and that's because of the limitation of available murine models. If you just inject a wild type mouse with ponatinib, nothing happens really. So what was your approach to finding relatively good murine models? How did you go about that?   Hind Lal:                     So this is the top scientific question you can ask. So like science, the field is try and try again. So initially this is the first paper with the ponatinib toxicity using the real in vivo models. Any paper before this including ours studies published, they were done on the cellular model in hiPSC, that isolated cardiomyocytes. So you directly putting the ponatinib directly the isolated cells. So this is first case when we were trying to do in vivo, maybe other attempt in vivo but at least not published. So first we also treated the animals with ponatinib and that failed, we don't see any cardiotoxic effect. And then when we going back to the literature, the clinical data is very, very clear from pharmacovigilance that ponatinib is cardiotoxic in humans. So when we're not able to see any phenotype in mouse, we realize that we are not mimicking what's happening in the humans.   So we certainly missing something. Now once again I quote this COVID-19, so many people get infected with COVID-19 but people are having preexisting conditions are on high risk to developing CVD. So there was some literature on that line. So we use this very, very same concept that if there is preexisting conditions, so likely who'd have developing future cardiac event will be more. So we use two model in this paper one atherosclerosis model which is APoE null mice mice, another is tag branding which is pressure overload model for the heart and as soon as we start using what we call comorbidity model like patient is having some preexisting conditions and we very clearly see the robust defect of ponatinib on cardiac dysfunction.   Cindy St. Hilaire:        Yeah, it's really, really well done and I really like that you use kind of two different models of this. Do you think it's also going to be operative in maybe like the diabetic mirroring models? Do you think if we expand to other comorbidities, you might also recapitulate the cardiotoxicity?   Hind Lal:                     So you got all the best questions.   Cindy St. Hilaire:        Thank you. I try.   Hind Lal:                     So because this is CML drug and lot of the risk factor for cardiovascular and cancer are common and even metabolic disease. So most of the time these patients are elderly patients and they're having metabolic conditions and most of the time they have blood pressure or something CVD risk factors. So I agree with you, it'll be very relevant to expand this to the diabetes or metabolic models, but these were the first study, we put all our focus to get this one out so news is there then we can expand the field adding additional models et cetera. But I agree with you that will be very logical next step to do.   Cindy St. Hilaire:        Yeah. And so I guess going back to what you know from the human study or the clinical trials or the human observations, are different populations of patients with CML more predisposed to cardio toxicity than others or is that not known yet?   Hind Lal:                     So one other area called pharmacovigilance. So what pharmacovigilance does patient all over the world taking these drugs. So WHO have their own vigilance system and FDA have their own, so it's called BG-Base for the WHO and it's called the FAERS for the FDA. So one can go back in those data sets and see if X patient taking this Y drug and what kind of symptoms or adverse effect they are seeing and if these symptoms are associated with something else. So there is data that if patients having CVD risk factor, they are more prone to develop ponatinib induced cardiac events. But it needs more polish like you asked the just previous question, diabetes versus maybe blood pressure means hypertension, atherosclerosis, or thrombosis. So it has not been delineated further but in a one big bucket if patients are having CVD risk factor before they are more prone and more likely to develop the cardiac events.   Cindy St. Hilaire:        So after you established that these two murine models could pretty robustly recapitulate the human phenotype, what did you do next? How did you come upon the S100A8/A9-NLRP3-IL-1β signaling circuit? How did you get to that?   Hind Lal:                     So in basic science work, whenever we do mouse is called until we get there is cardiac dysfunction, it's called phenotype, right? So mouse had a cardiac phenotype. So next step is, "Why? What is leading to that phenotype?" That's what we call mechanism. So there the best idea to fit the mechanism is using one of the unbiased approaches like you do unbiased proteomics, unbiased RNC analysis, something like this that will analyze the entire transcript like RNC and say, "Okay, these pathway are," then you can do further analysis that will indicate these pathway are different, are altered. So in this case we used RNC analysis and it came out that this yes A8 and yes A9, 100A8 and nine, they were the most upregulated in this whole set. And thereafter we were very lucky. So we started this study at Vanderbilt, where my lab was and thereafter we very lucky to move here and found Sultan who had a lot of experience with this inflammation and immune system and then Sultan may add something on this so he'll be the better person to say something on this.   Tousif Sultan:              So after our RNC analysis, so we got this S100A8 and nine as top hit with the ponatinib treatment. So then we validated this finding with our flow cytometric, qRT PCR aand then we started which pathway is going to release cytokine and all that. So we found that is NLRP3 inflammasome.   Cindy St. Hilaire:        Yeah and well and I guess maybe step back, what is S100A8/A9? What are those? Tousif Sultan:              Yeah, S10A8/A9 is a calcium binding protein. So that's also called alarmin and they basically binds with the pathogen associated pattern and other TLR2 like receptors and then start inflammatory pathway to release cytokine and all that and it's stable in heterodimer form. So S100A8 heterodimer with A9 and then bind with TLR and a start in this inflammatory pathway.   Cindy St. Hilaire:        And what type of cell is that happening in? Is that happening in the immune cells only or is it also in the cardiomyocyte, or...?   Tousif Sultan:              Yeah, we have included all this data. So from where this alarmin is coming with ponatinib treatment, so literature also suggested that neutrophils and monocytes, those cells are the potential to release the alarmin. So here we also found these two type of cells, neutrophils and monocytes. They release huge alarmin with the treatment of ponatinib.   Cindy St. Hilaire:        And so really taking this really neat mechanism to the next level, you then tried attenuating it by using broad anti-inflammatory steroid dexamethasone but also by targeting these specific components, the NLRP and the S100A specific inhibitors and they worked well. It worked really nicely. Does your data show that any of these therapies work better than the other and then are these viable options to use in humans?   Hind Lal:                     Yeah, we have some data in the paper. Are very broad which help a lot in COVID patients, far very acute infections. So in this case, situation is very different cause most of CML patients will going to take ponatinib for lifelong, there is no remission, right? So in those case, its certainly not a very attractive option. We have shown data in the paper that dexamethasone help with the heart but lead to some metabolic changes. So we have compared those with the NLRP3 inhibitors, those metabolic alterations, dexa versus the NLRP3 inhibitors, CY-09. And we demonstrated that targeting is specifically with paquinimod, our NLRP3 inhibitor CY-09, feel better. It can still rescue the cardiac phenotype without having those adverse effect on metabolic parameters.   Cindy St. Hilaire:        That's wonderful. Do you think though that because you have to take ponatinib for life, that long-term NLRP inhibition would also cause problems or...?   Hind Lal:                     So because not every patient who taking ponatinib would develop the cardiac phenotype, right? Which is like a 10%, 12%, patient developing cardiac dysfunction. So I think someone like I strongly believe paquinimod, which is inhibitor of S100A9, will be really good option or at least we have enough data that make us nail for at least a small clinical trial. And we quickly moving on that. At UAB we have our clinical cardio-oncology program and we are already in touch with the director for the clinical cardio-oncology program. So what we trying to do in that small trial is if one of the standard therapy for heart like beta blocker or ARBs inhibitor, is there any preference like one work better than the other in the standard care? So first we doing that project, then we obviously looking forward if one small clinical trial can be done with paquinimod. I strongly believe it should be helpful.   Cindy St. Hilaire:        That is wonderful. And so do you think... There's other chemotherapeutic agents or probably even other non-cancer drugs that cause cardiotoxicity, do you think this mechanism, this pathway, this S100A-NLRP-IL-1β axis is operative in all cardiotoxicities or do you think it's going to be very specific to the ponatinib?   Hind Lal:                     So it's certainly not all, but it'll be certainly more than ponatinib. So in our lab we are using another kinase inhibitor, which is osimertinib and it's not published yet, but now we know that it's also cardiotoxic because it's taking metabolic root or energetics disruption but not this pro-inflammatory part, but we're doing another project which is strep pneumonia induced cardiac dysfunction, which is called pneumonia. So strep pneumoniae, which leads to the pneumonia ,and lot patient die because of the failing heart we see here in the hospitals and we see these pathways operational over there and we gearing up to do clinical trial on that aspect as well, but it's not generalized like all kind of heart will have the same mechanism.   Cindy St. Hilaire:        It's wonderful to see you're already taking those next steps towards really kind of bringing this to a translational/clinical study. So what was the most challenging aspect of this study?   Tousif Sultan:              The challenging aspect, ponatinib is a kinase inhibitor and that was surprising for us how it's activating immune cells. Generally kinase inhibitors, inhibits all the cells like that. So that was challenging. So we repeated it many times did in vitro experiment to confirm that. So we just added, just treated in vitro immune cells with the ponatinib and confirmed it. So that was little challenging.   Cindy St. Hilaire:        So what's next? You mentioned you're going to try some clinical trials, early stage clinical trials. What's next mechanistically, what do you want to go after?   Hind Lal:                     So what we are doing next and we are very, very eagerly trying to do that. So what it was done, we used the cardiac comorbidity models, but as you know, anybody who will take ponatinib will have cancer, right? So we strongly believe that we miss one factor. There was no cancer on these. So that is very logical next step. What that will allow us to do, what rescue experiment we'll have done in this paper. So we saw, "Okay, this rescue the cardiac phenotype, which is taken care of now," but very same time, we not able to demonstrate that this is happening without hurting the cancer efficacy. So if we have the dual comorbid mouse, which have CML a real thing and we have cardiac thing, then that will allow us to demonstrate, "Okay, we got something that can take care of the cardiac problem without hurting the efficacy on the cancer." And it will be best if you also help little bit to more potentiate the cancer efficacy.   Cindy St. Hilaire:        Yes. Excellent. Well, congratulations on a beautiful study, really exciting findings. Dr Lal and Dr Sultan, thank you so much for taking the time to talk with me today.   Tousif Sultan:              Thank you so much.   Hind Lal:                     Well thank you, Cynthia. We really appreciate your time. Thank you for having us.   Cindy St. Hilaire:        Yeah, it was great.   Cindy St. Hilaire:        That's it for our highlights from the February 3rd and February 17th issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Hind Lal and Dr Tousif Sultan. This podcast is produced by Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team at Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, you're on-the-go source for most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2023. And the opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.  

In this JCO Precision Oncology Conversations podcast, JCO PO author Dr. Thanh Dellinger of City of Hope National Medical Center shares insights into the research published in her article, “Hyperthermic Intraperitoneal Chemotherapy–Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.” Podcast host Dr. Abdul Rafeh Naqash talks with Dr. Dellinger about hyperthermic intraperitoneal chemotherapy (HIPEC) and the various challenges of the treatment of epithelial ovarian cancer (EOC). The study described in this JCO PO article discusses protein expression, RNAseq alterations and signature, and whole-transcriptome sequencing and signatures. Read here  https://ascopubs.org/doi/full/10.1200/PO.21.00239   TRANSCRIPT Dr. Abdul Rafeh Naqash: Welcome to ASCO's Precision Oncology Conversations where we bring you the highlights and overview of precision oncology. This podcast is here to provide interactive dialogue focusing on the excellent research published in the JCO Precision Oncology. Our episodes will feature engaging conversations regarding precision oncology with the authors of a clinically relevant and highly significant JCO Precision Oncology article. You can find all our shows including this one at asco.org/podcasts, or wherever you get your podcasts. Hello, I am Dr. Abdul Rafeh Naqash. I'm a medical oncologist and a phase one clinical trialist at the OU Stephenson Cancer Center. You're listening to JCO Precision Oncology Conversations. I have no conflicts of interest related to this podcast. A complete list of disclosures is available at the end of each episode. Today, I will be talking with Dr. Thanh Dellinger from the City of Hope Comprehensive Cancer Center, who's a gynecological oncologist, and we'll be talking about her JCO Precision Oncology article, ‘Hyperthermic Intraperitoneal Chemotherapy-Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.' Dr. Dellinger does not have any conflicts of interest. Hi, Dr. Dellinger, welcome to our podcast! Dr. Thanh Dellinger: Hi, Dr. Naqash! It's such a pleasure to be on with you. Dr. Abdul Rafeh Naqash: We recently saw your paper published. It's one of those interesting, clinical translational papers that we felt needed to be highlighted in our Precision Oncology Podcast series. So, we're really excited to have you here today to take a deeper dive into the findings and some of the novel approaches that you used in your recent publication. So, for starters, could you give our listeners a brief idea of what HIPEC is, where it's used, and when it's used in ovarian cancer? Dr. Thanh Dellinger: Right! Thank you very much for this great introduction. So, HIPEC or Hyperthermic Intraperitoneal Chemotherapy has been used in ovarian cancer for quite some time. The most relevant data giving us an indication for ovarian cancer was published by Dr. van Driel in the OVHIPEC-1 randomized trial several years ago in the New England Journal of Medicine, which demonstrated that in stage 3 ovarian cancer patients who undergo an interval tumor debulking with HIPEC, that those patients appear to enjoy both progression-free and overall survival benefit. In fact, the overall survival benefit is nearly 12 months for those patients. So, with this in mind and a number of other data, the HIPEC treatment for those patients that interval debulking has been incorporated into the NCCN guidelines. Nonetheless, there have been some criticisms of HIPEC and it still remains to be seen who those patients are, the ovarian cancer patients who really best benefit from HIPEC, given the morbidity of HIPEC. We now know also that HIPEC is probably equivalent to just cytoreductive surgery alone in terms of morbidity. Dr. Abdul Rafeh Naqash: Thank you for that explanation. And especially for people like myself, who are not surgeons or gynecological oncologists, that was very helpful. So, my next question, and you probably partly answered it, but I'm going to still ask the question is: what is the reason you think that intraperitoneal chemotherapy overall, has not been as widely adopted? Dr. Thanh Dellinger: You touch on a very good point there. As many of the listeners may understand, IP chemotherapy has demonstrated a lot of efficacies in multiple clinical trials over the last decade or two decades even. And part of why, despite its benefit, it has not been taken up in the overall community may really be the difficulty and the complexity of doing IP chemotherapy in the community, especially the side effects are difficult sometimes to take care of. There's increased abdominal pain and there are catheter issues. And so, especially with more recent data, that with the presence of Avastin, IP chemotherapy may not necessarily be as beneficial. Unfortunately, IP chemotherapy hasn't been really taken up in daily oncologic care with ovarian cancer. Nonetheless, we know that there are a lot of theoretical benefits because of the peritoneal metastasis not being as best treated with intravenous chemotherapy as with regional therapy. Dr. Abdul Rafeh Naqash: Thank you! So, now going to the data that you published. I was very intrigued with some of the findings. And from what I understood, your main aim was to understand predictive biomarkers to identify patients or basically identify molecular characteristics for patients' selection for HIPEC. So, could you tell us more about why you initiated this study? And I understand this is one of the, I believe the first study in humans to evaluate some of these interesting biomarkers, both pre- and post-. So, what was the background of doing this trial? And what led to this interesting study? Dr. Thanh Dellinger: Thank you for pointing out this aim. There's a lot of criticism of HIPEC and part of it is that we may not exactly understand the mechanisms of HIPEC, why is it that it works so well in some patients? There's a lot of preclinical data supporting hyperthermia, especially with cisplatin. There's synergy between cisplatin and hyperthermia, and improving the DNA adduct formation. There's increased cytotoxicity seen when the temperature increases up to 43 degrees. And there's also a T-cell activation and immune response that occurs during hyperthermia. So, a lot of this, however, has been done in preclinical studies, in vitro data as well as preclinical mouse models. There hasn't been much or really anything published that, as far as I know, has been done in humans. And so, this particular study looked at both pre-treatments, pre-HIPEC specimens, peritoneal biopsies, as well as immediate post-operative peritoneal biopsies, tumors, and normal samples, and we wanted to look both at the whole transcriptomic sequencing profile, but also at the tumor microenvironment. Dr. Abdul Rafeh Naqash: From a logistic standpoint, from a trial design standpoint, was this a phase 1 study? I know you use the term pilot in the publication. So, were you trying to look at safety also, or was this primarily I would say, a biomarker, pharmacodynamic biomarker-driven study that you were trying to evaluate? Dr. Thanh Dellinger: You're correct. This was essentially a feasibility study. But we additionally looked at safety and feasibility with HIPEC at our institution. And in some respects, we also looked at the feasibility of giving intraperitoneal chemotherapy normothermically early after HIPEC, and so it was also an endpoint to look at safety. Dr. Abdul Rafeh Naqash: Understand! I believe there was some difference in the dose for the cisplatin, I believe, is the chemotherapy that you use. What was the rationale for the difference in the dose for 75 milligrams per meter square that you use in your study? Dr. Thanh Dellinger: The study was initiated at a time before the OVHIPEC-1 trial was published. And so, at that time, the HIPEC dose for cisplatin was still not established. 75 milligrams per meter square for cisplatin was actually used in other trials, and has been noted to be effective in other clinical trials. Dr. Abdul Rafeh Naqash: Thank you! Now going to the patient population for this trial. What type of patients were you enrolling? Was it just epithelial ovarian cancer patients, did these patients need to have peritoneal metastases when you were doing this cytoreductive surgery? What was the patient population that you were targeting in this trial? Dr. Thanh Dellinger: The majority of the patients did have epithelial ovarian cancer. We did enroll a few, actually 5, uterine cancer patients as well, which were not included in this specific publication. But the majority of them were epithelial ovarian cancer patients. Dr. Abdul Rafeh Naqash: Going to the interesting translational analysis. So, you had three subsets of patients based on the biopsy collection. What were your hypotheses, and what drove some of those translational studies to understand the biomarkers? Dr. Thanh Dellinger: The first translational analysis we conducted was the whole transcriptomic sequencing, and specifically, we wanted to look, one, for any potential transcriptomic signatures that may correlate with survival or improved response to HIPEC. The second one was to look at whole exome sequencing. Thirdly, we looked at whole transcriptomic sequencing differences before and after HIPEC treatment. And lastly, we looked at the tumor microenvironment through multiplexing of certain markers associated with T-cell response. Dr. Abdul Rafeh Naqash: From a clinical outcome standpoint - and we'll discuss the biomarkers in more detail - from a clinical standpoint, when I briefly looked over the PFS curves, were the results, as far as expected outcomes, were they similar to what you see with the current standard? Or were there any unusual safety signals? Or would you attribute any of the adverse events that you saw to intraperitoneal chemotherapy specifically? Because I believe some patients did have some chemotherapy pre-surgery, neoadjuvant if I'm correct. So, how would you attribute some of those AEs, and if at all, did you see any interesting safety signals of concern and outcomes as far as PFS is concerned? Dr. Thanh Dellinger: So, one of the major toxicities that we saw in the first half of our trial were actually renal toxicities. In fact, there were actually two patients who could not go on to adjuvant chemotherapy because they suffered chronic renal failure. And because of that, halfway through the trial, we did actually add a nephro protectant called sodium thiosulfate. And this actually dramatically improved those renal toxicities. And for the second half of our study, no patients suffered grade three or grade four renal adverse events. And so, that did change significantly. Dr. Abdul Rafeh Naqash: From a genomic standpoint, it's very interesting that you were able to do all these very cool and interesting translational biomarker studies, including multiplex immunofluorescence. From a genomic standpoint, though, would you say it's fair to say that there was no significant correlation based on the baseline genomics for some of the patients and their outcomes? Is that a fair assessment? Dr. Thanh Dellinger: Yes, that is a very fair assessment. I think that our cohort was really too small to make those kinds of assessments. I don't know whether you saw there recently was a paper published by the OVHIPEC-1 group looking at their cohort of over 200 patients that underwent the interval cytoreductive surgery in HIPEC and they did actually demonstrate benefit in patients who are HIV-positive but BRCA wild-type, but not necessarily in BRCA mutated patients. So, I think that I would point to that study to look for genomic effects with HIPEC patients. Dr. Abdul Rafeh Naqash: Understand. Now, again, going to the biomarkers that your team evaluated, it seems from among good responders especially, you saw an increase in tumor necrosis factor, alpha signaling, NF-kappa B signaling, KRAS signaling, and then you also saw some pathways that were downregulated, especially the G2-M checkpoint, and Myc targets. What would you say the correlation of these is in terms of future drug development in this specific setting? Dr. Thanh Dellinger: I think that we did see some increase in immune pathways in patients who did better in the end. And also, our multiplex results did demonstrate that E1 expression was increased in patients who had better responses after HIPEC. So, our hypothesis is that potentially, there's an activation of T-cell response with HIPEC and that potentially PD-1 inhibitor could be added in the future. This is a hypothesis that certainly would need to have more work, but it's something that is interesting enough to really look at in ways of how to improve HIPEC. Dr. Abdul Rafeh Naqash: Going to your point on the PD-1, I found really intriguing that you were able to see an increase in PD-1 expression on CD8+ T cells but no actual increase in the number of CD8+ T cells suggesting there's some sort of activation of this marker and this may not necessarily be a marker for T-cell exhaustion. So, would you interpret it in a way that in a different setting, perhaps a new adjuvant approach with immunotherapy, would perhaps somehow augment this and then you could see more upregulation? Is there any work being done in that field? How would you put this in the context of your findings? Dr. Thanh Dellinger: You bring up a really great point because to date HIPEC has been demonstrated to have benefit in the interval setting. But there was a more recent study done by, well not recent, a more recently published study by a Korean group that demonstrated no benefit in the adjuvant setting for HIPEC and still some benefit in the interval setting. And the question is, are these really two different types of cohorts who respond differently because of potential differences in immune response and tumor microenvironment? I think that that would be a great way of delving further into this. What are really the differences in tumor microenvironment changes in those two different settings? Dr. Abdul Rafeh Naqash: Definitely! It's very exciting. You've also shown upregulation of, as you mentioned earlier, immune pathways, as well as upregulation of genes related to heat shock proteins. Does that play into future drug development as far as HSP Inhibitors are concerned? Dr. Thanh Dellinger: That is a really great question. Certainly, in preclinical models, heat shock proteins are known to be elevated and they do activate dendritic cells and result in T-cell activation. Now, whether that can be spelled out into actually some future drug therapy definitely remains to be seen. To date, there hasn't been any success in using heat shock types of agents or inhibitors, unfortunately. So, I think while this is of great interest, I'm not entirely sure that this will translate into any drug therapy in the future. Dr. Abdul Rafeh Naqash: And I totally connect with you there as a phase 1 trialist. I completely agree that we see a lot of translational data, more often than not, going into the phase 1 site because many of these targets are not actionable. Now, from a DNA repair standpoint, you did see that there was interference with DNA repair, as far as some of the analyses that you did, but I did not specifically see any markers for DNA damage that were assessed on the biopsies such as Gamma-H2AX, RAD 51, or Phospho-NBS. Was there a reason why that was not looked at? Dr. Thanh Dellinger: I think that we did look at that and there weren't really any significant results. We did put some of the data into the supplementary data. I think that in the end, our cohort was really too small to really make any meaningful data. But I absolutely agree with you looking at HSP and DNA repair is really important. And as I mentioned that most recently published paper does address that. Dr. Abdul Rafeh Naqash: Excellent! Do you think that there could be any confounders in this analysis that could have led to the upregulation of some of these pathways and may not necessarily have been the intraperitoneal chemotherapy? Could you think of some other reasons that this could have been a confounding factor? Or would it primarily be attributed to the intraperitoneal chemotherapy that you guys have looked at in this interesting paper? Dr. Thanh Dellinger: Yeah, it is a rather small cohort. So, I think that more data is required to potentially repeat this in the larger cohort. But what is interesting is that we did have paired analysis. So, we had matched peritoneal samples from the same patients looking before the HIPEC and after the HIPEC, which is very unique and hasn't really been done in the setting before. And while you couldn't necessarily repeat the same exact peritoneal tumor it was very close. And so, in the best setting, I think that we did have a good paired analysis. Dr. Abdul Rafeh Naqash: That was one of the very interesting aspects of this study that I very much appreciated, that you were able to get some of those paired biopsies and do the analyses on samples and look at all these markers. So, this was all excellent work and definitely intrigues the mind into what other ways one could use some of these findings to develop future combination-based approaches, whether it's the neoadjuvant or the adjuvant setting for patients with ovarian cancer. Are there any next steps as part of this project that you are excited about that you can share? Dr. Thanh Dellinger: Right! I'm definitely very excited about trying to build on this and essentially developing a much larger predictive study using hundreds of ovarian cancer HIPEC-treated tumors in collaboration with others. We have definitely developed a great community of HIPEC investigators who are very interested in developing somewhat of a predictive signature for ovarian cancer undergoing HIPEC. So, I'm very excited to hopefully be able to develop this consortium of HIPEC transcriptomic research. And so, I'm looking forward to collaborating with my co-investigators on that. Dr. Abdul Rafeh Naqash: It was definitely exciting to talk to you about your work. Now, I want to ask you about you as an investigator or as a researcher. How did you end up in this field? What was your background while you were pursuing science and medicine? How did you end up in this field and how are you mentoring the next generation? Dr. Thanh Dellinger: When I was a fellow at UCI, my mentor Robert Bristow introduced me to HIPEC and that has really stuck. As a GYN oncologist, it is hard to really do both chemo and be a good surgeon. And in many ways, I have really specialized in surgical oncology more than in medical oncology. And HIPEC is really a very nice blend of the two. It allows you to do clinical trials while still doing surgery and giving some chemotherapy. Really, it was for the introduction of my more recent mentor, Elena Rodriguez, who really introduced me to genomics and applying this to HIPEC samples that this all came about. And so, I think that there are a lot of opportunities for surgical oncologists who do not give chemo and may think that clinical research is not for them, but there are a lot of translational opportunities and clinical trial opportunities for those who don't give chemotherapy, but are surgical oncologists. Dr. Abdul Rafeh Naqash: Thank you so much. We are really excited for all the work that you're doing and will continue to do and hopefully, we'll see more of this evolve as time progresses. Dr. Thanh Dellinger: Thank you so much, Dr. Naqash. It was such a pleasure meeting you and talking to you. Dr. Abdul Rafeh Naqash: Same here. Thank you for listening to JCO Precision Oncology Conversations. To listen to more, visit asco.org/podcasts, or find them on Google Play Spotify and Apple podcasts. To stay up to date, be sure to follow and share JCO Precision Oncology content on Twitter. The Twitter handle is @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journals/PO. 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.  Guest Bio Dr. Thanh Dellinger, MD, is a gynecologic oncologist and physician-scientist who specializes in ovarian and uterine cancer. She is an expert in hyperthermic (HIPEC) and pressurized aerosolized intraperitoneal chemotherapy (PIPAC), and is the primary investigator of clinical and translational studies focusing on these therapies. She received her medical degree at University of California Irvine, where she also completed a gynecologic oncology fellowship. She is leading the first U.S. clinical trial in PIPAC (pressurized intraperitoneal aerosolized chemotherapy), a novel therapy using pressurized aerosolized chemotherapy for ovarian cancer. Her current research focuses on innovative therapies for ovarian cancer using intraoperative chemotherapy, and novel antibody and nanoparticle therapies.

Hyperthermic intraperitoneal chemotherapy (HIPEC) delivers chemotherapy directly into the abdominal cavity. It is used in conjunction with cancer surgery for people with advanced cancer that has spread inside the abdomen. “Hyperthermic” means warm or hot. “Intraperitoneal” means inside the abdominal cavity, which is encased in a sac called the peritoneum. HIPEC uses high-dose chemotherapy to kill microscopic cancer cells inside the abdominal cavity. The HIPEC procedure is performed immediately after a surgeon has removed all visible cancer in the abdomen. HIPEC is well studied in several types of cancer and being explored as a potential treatment in others. "So really any cancer that's just localized in the abdomen on the surface of the peritoneum could be a candidate," explains Dr. Travis Grotz, a Mayo Clinic surgical oncologist. "We know for sure, based on studies and data that HIPEC works well for cancers of the colon, cancers of the appendix, cancer to the ovaries, cancer of the stomach, and there's even a cancer of the lining of the peritoneum, called mesothelioma. So those would be the cancers I think that are well studied and well accepted. Then, there are more rare tumors that we have less data for, such as cancer to the pancreas or gallbladder or small intestine, that we don't know yet if that's the right treatment."The specific type of chemotherapy used for HIPEC varies depending on the type of cancer being treated. The abdominal cavity is bathed with hot chemotherapy to kill any microscopic cancer cells that might still be present. Heating the chemotherapy enhances its effectiveness because, when it's hot, chemotherapy penetrates the tissue more deeply, increasing the number of cancer cells it can reach.On this Mayo Clinic Q&A podcast, Dr. Grotz explains what HIPEC is, how it is performed, and the risks and benefits of the treatment.Related Articles: "New therapies bring hope for ovarian cancer." "Alternative chemotherapy offers hope for late-stage cancers." "Aggressive treatment turns tide in fighting colon cancer."

Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay. For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also.After a little break, I am back with more information on injections, today the focus will be on sub cutaneous route of drug administration, I will be narrating important features, advantages, disadvantages and I will discuss different dosage forms for this route like dermojet, implants, etc. Next in my list I will cover Intraperitoneal, Intrathecal, Intracardiac, and in the same line their separate features, advantages and disadvantages and not to be forgotten, examples are always must, they complement all the discussions with full flash bundle of information, something just that cannot be missed, forgotten or left untalked. This description marks the essence of examples, hope you understand the depth of all these, I am sure you do!! You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!!

Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay. For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also. After a little break, I am back with more information on injections, today the focus will be on sub cutaneous route of drug administration, I will be narrating important features, advantages, disadvantages and I will discuss different dosage forms for this route like dermojet, implants, etc. Next in my list I will cover Intraperitoneal, Intrathecal, Intracardiac, and in the same line their separate features, advantages and disadvantages and not to be forgotten, examples are always must, they complement all the discussions with full flash bundle of information, something just that cannot be missed, forgotten or left untalked. This description marks the essence of examples, hope you understand the depth of all these, I am sure you do!! You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!!

Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay. For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also.After a little break, I am back with more information on injections, today the focus will be on sub cutaneous route of drug administration, I will be narrating important features, advantages, disadvantages and I will discuss different dosage forms for this route like dermojet, implants, etc. Next in my list I will cover Intraperitoneal, Intrathecal, Intracardiac, and in the same line their separate features, advantages and disadvantages and not to be forgotten, examples are always must, they complement all the discussions with full flash bundle of information, something just that cannot be missed, forgotten or left untalked. This description marks the essence of examples, hope you understand the depth of all these, I am sure you do!! You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!!

Researchers are conducting the first U.S. trial of pressurized intraperitoneal aerosolized chemotherapy (PIPAC) for the treatment of peritoneal carcinomatosis in patients with gynecologic or gastrointestinal cancers. Coprincipal investigator Thanh H. Dellinger, MD, of City of Hope in Duarte, Calif., describes this trial and the PIPAC procedure to host David H. Henry, MD, in this episode. To start, the pair discuss a patient who might be eligible for PIPAC – one with stage 3 ovarian cancer. General approach to stage 3 ovarian cancer Therapy typically includes a combination of surgery and chemotherapy. The order in which chemotherapy is given, either pre- or postoperatively, depends on performance status and whether patients have extra-abdominal disease or parenchymal liver disease. Operative approaches, including debulking surgery, are pursued if believed to be optimal, meaning all gross residual disease can be resected. If all residual disease cannot be resected, patients are offered neoadjuvant chemotherapy, typically for three to four cycles before an interval debulking surgery, followed by postoperative adjuvant chemotherapy. Intraperitoneal chemotherapy Intraperitoneal (IP) chemotherapy is used to treat peritoneal surface malignancies. The peritoneum is a separate organ that is difficult to treat adequately with intravenous chemotherapy alone. Giving IP chemotherapy in combination with intravenous chemotherapy may be more effective than intravenous chemotherapy alone (N Engl J Med. 2006; 354:34-43; https://bit.ly/3g3lngx). However, there are many challenges in delivering IP chemotherapy, including increased side effects of abdominal pain and IP catheter failure. Recent clinical trials have shown that, with the addition of bevacizumab, the survival benefit with IP chemotherapy may not be as significant as prior trials suggested (J Clin Oncol. 2019 Jun 1;37[16]:1380-90; https://bit.ly/2VAmRVW). In general, IP chemotherapy has not been embraced by the medical oncology community as much other types of chemotherapies, Dr. Dellinger said. What is PIPAC? PIPAC is a novel therapy discovered by a German surgical oncologist, Marc A. Reymond, MD, from University of Tuebingen (Germany). PIPAC delivers chemotherapy at a reduced dose directly into the intraperitoneal cavity but in a pressurized and aerosolized form. PIPAC is done at the time of the diagnostic laparoscopy and requires a nebulizer for aerosolization of the chemotherapy as well as a high-pressure injector. This approach allows for the chemotherapy to be pushed deeper into tissues, compared with hyperthermic intraoperative peritoneal chemotherapy (HIPEC). With HIPAC, tissue penetration is typically 1 mm or less. With PIPAC, there is deeper penetration and better distribution of chemotherapy throughout the entire intraperitoneal cavity. With PIPAC, chemotherapeutic agents are given at a lower dose than is typically administered with IP or intravenous chemotherapy, which helps in reducing the toxicity. PIPAC is given every 6 weeks for three cycles, requiring three laparoscopic procedures. These laparoscopic procedures allow for the opportunity to obtain peritoneal tumor biopsies before and after to investigate the natural course of these tumors and their microenvironment. Toxicity of PIPAC PIPAC has been done in more than 800 patients with gastrointestinal and gynecologic cancers in Europe and Asia. Severe adverse events  have been minimal, with about 12%-15% grade 3/4 SAEs and very rare grade 5 SAEs. The most common side effect is typically abdominal pain, attributed to the IP administration in conjunction with the laparoscopic surgery. Renal toxicity is a concern with intravenous cisplatin use, but this has not yet been seen with PIPAC. With PIPAC, cisplatin is given at 10.1 mg/m2 and doxorubicin is given at 2.1 mg/m2, doses that are much lower than the typical doses for these drugs. PIPAC in clinical trials PIPAC clinical trials have moved into phase 2 in Europe for ovarian cancer, with a publication demonstrating an objective response rate of over 60% in platinum-resistant ovarian cancer (Gynecol Oncol. 2015 May;137[2]:223-8; https://bit.ly/2KY701r). A phase 3 trial of PIPAC was planned but was stalled because of the COVID-19 pandemic. Because of the need for Food and Drug Administration approval, researchers have just launched the first phase 1 trial of PIPAC in the United States. Phase 1 trial of PIPAC City of Hope is working with affiliates at Mayo Clinic in Jacksonville, Fla.; Northwell Health in New York; and the National Institutes of Health to enroll eligible candidates for a phase 1 trial (NCT04329494; https://bit.ly/3qs8H7U). Eligible candidates include those with gastric, uterine, colorectal, appendiceal, and ovarian cancer with evidence of peritoneal carcinomatosis who have failed at least one line of therapy. PIPAC is an outpatient procedure, but given the trial and need for monitoring, patients typically leave the hospital the following day after blood samples are obtained for the study. City of Hope has recruited seven patients since activating their study in August 2020, with a goal of enrolling 16 patients by spring 2021. Future directions Peritoneal tumor biopsies obtained during the laparoscopic procedures are being used to study the microenvironment of these cancers. In eventual phase 2 clinical trials, the researchers may include immune checkpoint inhibitors. Biomarker analyses are underway, looking at expression of PD-1 and tumor-infiltrating lymphocytes. The researchers are also studying the role of genomic sequencing and DNA repair. Disclosures: Dr. Dellinger and Dr. Henry have no financial disclosures relevant to this episode. Show notes by Sheila De Young, DO, resident at Pennsylvania Hospital, Philadelphia. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

Interview with Clayton C. Petro, MD, and Ajita S. Prabhu, MD, authors of Patient-Reported Outcomes of Robotic vs Laparoscopic Ventral Hernia Repair With Intraperitoneal Mesh: The PROVE-IT Randomized Clinical Trial

Interview with Clayton C. Petro, MD, and Ajita S. Prabhu, MD, authors of Patient-Reported Outcomes of Robotic vs Laparoscopic Ventral Hernia Repair With Intraperitoneal Mesh: The PROVE-IT Randomized Clinical Trial

Only a handful of hospitals in the country offer an innovative procedure known as HIPEC to treat rare forms of cancer.

Dr. Melanie Ongchin, surgical oncologist at the UPMC Hillman Cancer discusses the use of an innovative surgery known as HIPEC to treat peritoneal carcinomatosis, a rare type of cancer that can develop when gastrointestinal or gynecologic cancers spread. 

The HIPEC team at Penn Medicine is led by surgical oncologist Dr. Giorgos Karakousi. The HIPEC team includes specialists from medical oncology, anesthesiology, pathology, radiology, and critical care.Giorgos Karakousis MD, FACS discusses why HIPEC is usually performed at academic medical centers like Penn Medicine and shares what makes it one of the most innovative treatments available today for complex cancers.

Recurring guest Dr. Michael Valente provides insight into HIPEC, an alternative and innovative method of delivering chemotherapy used to treat cancers that have spread to the lining of the abdominal cavity. Unlike traditional chemotherapy that is delivered intravenously, HIPEC delivers chemotherapy directly into the abdomen. Listen to learn how the process works and when HIPEC is a recommended treatment option.

Interview with Guido Beldi, Consultant Surgeon, author of Effectiveness of Prophylactic Intraperitoneal Mesh Implantation for Prevention of Incisional Hernia in Patients Undergoing Open Abdominal Surgery: A Randomized Clinical Trial

Interview with Guido Beldi, Consultant Surgeon, author of Effectiveness of Prophylactic Intraperitoneal Mesh Implantation for Prevention of Incisional Hernia in Patients Undergoing Open Abdominal Surgery: A Randomized Clinical Trial

Pediatric Grand Rounds for Wednesday, January 17, 2018 Andrea Hayes-Jordan, MD Chief, Pediatric Surgery/Pediatric Surgical Oncology Professor of Surgery and Pediatrics University of Texas MD Anderson Cancer Center

Researchers at Roswell Park Comprehensive Cancer Center have determined that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CS/HIPEC), a complex procedure to treat advanced abdominal cancers, can be done safely, and may be an effective therapy for select patients. In this fascinating segment, Valerie Francescutti, MD., disusses Cytoreduction Surgery and Hyperthermic Intraperitoneal Chemotherapy as a way to improve survival, surgical outcomes, and when to refer to a specialist.

Researchers at Roswell Park Comprehensive Cancer Center have determined that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CS/HIPEC), a complex procedure to treat advanced abdominal cancers, can be done safely, and may be an effective therapy for select patients. In this fascinating segment, Valerie Francescutti, MD., disusses Cytoreduction Surgery and Hyperthermic Intraperitoneal Chemotherapy as a way to improve survival, surgical outcomes, and when to refer to a specialist.

This episode features discussion on Heated Intraperitoneal Chemotherapy (HIPEC) treatment. The experts joining the podcast to discuss this type of care are Dr. Nelya Melnitchouk and Dr. Tom Abrams from the GI team at the Dana Farber/Brigham and Women's Cancer Center in Boston. HIPEC differs from other treatments because of the specific and targeted delivery method. The chemo does not circulate through the entire body during HIPEC. It only is directed at the cancerous cells in the abdomen area.

This episode covers Chapter 47 of Rosen’s Emergency Medicine. 1. List 6 general indicators of genitourinary trauma? Lower urinary tract and external genitalia   What are the four parts of the male urethra? What is the mechanism of an anterior urethral injury (at least 5 causes)? What is the mechanism of a posterior urethral injury? List 4 indications for retrograde urethrogram before foley placement? Describe the technique for a retrograde urethrogram? Classify bladder injuries and describe the mechanism of injury. Differentiate between extraperitoneal and Intraperitoneal bladder rupture Describe the indications and technique for retrograde cystogram? Outline the management of the different types of bladder injuries. List 3 clinical findings of a penile fracture Describe the management of penile Constricting devices Superficial hematoma Superficial lacerations Degloving injury Penile Fracture Penile amputation Blunt scrotal trauma Bites     Upper urinary tract   What is the presentation of a ureteric injury? What are the indications for renal imaging in an adult trauma patient? In a pediatric trauma ? Describe the management of renal injuries: Blunt Penetrating     Wisecracks:   What is the most common site of urethral injuries?

This episode covers Chapter 47 of Rosen’s Emergency Medicine. 1. List 6 general indicators of genitourinary trauma? Lower urinary tract and external genitalia   What are the four parts of the male urethra? What is the mechanism of an anterior urethral injury (at least 5 causes)? What is the mechanism of a posterior urethral injury? List 4 indications for retrograde urethrogram before foley placement? Describe the technique for a retrograde urethrogram? Classify bladder injuries and describe the mechanism of injury. Differentiate between extraperitoneal and Intraperitoneal bladder rupture Describe the indications and technique for retrograde cystogram? Outline the management of the different types of bladder injuries. List 3 clinical findings of a penile fracture Describe the management of penile Constricting devices Superficial hematoma Superficial lacerations Degloving injury Penile Fracture Penile amputation Blunt scrotal trauma Bites     Upper urinary tract   What is the presentation of a ureteric injury? What are the indications for renal imaging in an adult trauma patient? In a pediatric trauma ? Describe the management of renal injuries: Blunt Penetrating     Wisecracks:   What is the most common site of urethral injuries?

HIPEC, or heated intraoperative peritoneal chemotherapy, is an alternative method of delivering chemotherapy. Instead of infusing the medications through a vein, the chemotherapy is circulated in the abdominal cavity at the time of surgery. This allows direct treatment of certain cancers which have spread throughout the abdomen.At City of Hope, our peritoneal surface malignancy team consists of a multidisciplinary group of experts in the field. We are one of the busiest HIPEC centers in Southern California, and continue to push the envelope in treating these difficult cancers. The team will evaluate your case and present options. Not everyone will be a candidate for HIPEC and aggressive surgery, but other treatments may be available.Byrne Lee, M.D is here to explain how studies are showing that HIPEC with aggressive surgery improves survival in some cancers when compared to chemotherapy alone.

Dr Mackay speaks with ecancertv at ASCO 2016 about ovarian cancer, and the therapeutic potential of added intraperitoneal (IP) chemotherapy. IP chemotherapy allows the delivery of higher doses of chemotherapy to the tumour, while sparing other parts of the body from side effects. For women who were initially treated with chemotherapy prior to surgery (eg., neoadjuvant therapy), the initial results from a randomised phase II trial show that 23.3% of women who received IP and IV chemotherapy had disease progression at nine months, vs. 42.2% of those who received IV chemotherapy alone.

This podcast will examine data on utilization, toxicity and survival outcomes with the use of intraperitoneal chemotherapy for initial treatment of ovarian cancer at six NCCN institutions.

Host: Lee Freedman, MD Heated/Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is one of the most innovative treatments available today for complex abdominal cancers. What is it? Who is a candidate? And, what are the expected outcomes for our patients? Host Dr. Lee Freedman welcomes Dr. Giorgos Karakousis, Assistant Professor of Surgery at the Hospital of the University of Pennsylvania to discuss HIPEC.

Host: Lee Freedman, MD Heated/Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is one of the most innovative treatments available today for complex abdominal cancers. What is it? Who is a candidate? And, what are the expected outcomes for our patients? Host Dr. Lee Freedman welcomes Dr. Giorgos Karakousis, Assistant Professor of Surgery at the Hospital of the University of Pennsylvania to discuss HIPEC.

Abstract Considering the globally increasing rate of incidence, Type 2 diabetes mellitus belongs to the most frequent endocrine metabolic disorders today. In addition to insulin resistance of peripheral tissues, this disease is the result of dysfunction of the endocrine pancreas and in particular of the functional failure of β-cells. The progress of therapeutical strategies is based on the research of the underlying mechanisms. The aim of the present dissertation was the analysis of new molecular regulators which might improve our underdstanding of the differentiation of pancreatic islets and the functional maintenance of adult β-cells. The first part of this work concerned the role of the transcription factor Pax6 and especially the role of its transactivation domain (TA) and of its two DNA binding domains, the paired domain (PD) and the homeodomain (HD), in differentiation of pancreatic endocrine cells. By analyzing four different mouse lines with specific mutations in one of these three domains, we found that the PD of Pax6 is essential for differentiation of glucagon producing α-cells. Inactivation of this domain resulted in a phenotype similar to that of Pax6 knockout mice (Pax6-/-) with a near complete absence of glucagon positive α-cells, a markedly reduced number of insulin producing β-cells, and a disorganized islet structure. Mutations of HD or TA showed a less severe pancreatic phenotype. Islets either exhibited no morphological changes or they showed a reduction of α- and β-cells. Intraperitoneal glucose tolerance tests demonstrated the utmost importance of the transcription factor Pax6 for maintenance of normal pancreatic endocrine function in adult animals. In the second part of this study we identified new genes and proteins, respectively, which could play a regulatory role in normal function of β-cells. In particular it was possible to show that Eny2, hitherto a protein only described in yeast or invertebrates like drosophila, is involved in the regulation of insulin secreting vertebrate cells. si-RNA mediated knockdown of Eny2 resulted in markedly increased glucose and incretin-induced insulin secretion. This could be at least in part attributed to a higher glucose-dependent cellular metabolism and an enhanced signal transduction via protein kinase A and is accompanied by elevated levels of intracellular calcium. Taken together, these results indicate that Eny2 functions as a negative regulator of glucose-stimulated and incretin-mediated insulin secretion, at least in vitro. However, a gap of knowledge still remains between the established nuclear functions of Eny2 and the cellular phenotype we observed upon its suppression. Nevertheless, the effects of an Eny2-knockdown are glucose dependent and additive to the incretin signaling. This feature makes this model attractive to obtain new insights in how insulin secretion of β- cells proceeds and how to find new therapeutical strategies to treat type 2 diabetes mellitus.

The CIAO Study is a multicenter observational study currently underway in 66 European medical institutions over the course of a six-month study period (January-June 2012). This preliminary report overviews the findings of the first half of the study, which includes all data from the first three months of the six-month study period. Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study. 912 patients with a mean age of 54.4 years (range 4-98) were enrolled in the study during the first three-month period. 47.7% of the patients were women and 52.3% were men. Among these patients, 83.3% were affected by community-acquired IAIs while the remaining 16.7% presented with healthcare-associated infections. Intraperitoneal specimens were collected from 64.2% of the enrolled patients, and from these samples, 825 microorganisms were collectively identified. The overall mortality rate was 6.4% (58/912). According to univariate statistical analysis of the data, critical clinical condition of the patient upon hospital admission (defined by severe sepsis and septic shock) as well as healthcare-associated infections, non-appendicular origin, generalized peritonitis, and serious comorbidities such as malignancy and severe cardiovascular disease were all significant risk factors for patient mortality. White Blood Cell counts (WBCs) greater than 12,000 or less than 4,000 and core body temperatures exceeding 38 degrees C or less than 36 degrees C by the third post-operative day were statistically significant indicators of patient mortality.

The CIAO Study ("Complicated Intra-Abdominal infection Observational" Study) is a multicenter investigation performed in 68 medical institutions throughout Europe over the course of a 6-month observational period (January-June 2012). Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study. 2,152 patients with a mean age of 53.8 years (range: 4-98 years) were enrolled in the study. 46.3% of the patients were women and 53.7% were men. Intraperitoneal specimens were collected from 62.2% of the enrolled patients, and from these samples, a variety of microorganisms were collectively identified. The overall mortality rate was 7.5% (163/2.152). According to multivariate analysis of the compiled data, several criteria were found to be independent variables predictive of patient mortality, including patient age, the presence of an intestinal non-appendicular source of infection (colonic non-diverticular perforation, complicated diverticulitis, small bowel perforation), a delayed initial intervention (a delay exceeding 24 hours), sepsis and septic shock in the immediate post-operative period, and ICU admission. Given the sweeping geographical distribution of the participating medical centers, the CIAO Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections (IAIs) throughout Europe.

Übergewicht hat in den letzten Jahrzehnten weltweit epidemischen Charakter erreicht. In Europa sind bereits 43% der erwachsenen Bevölkerung übergewichtig und 17% fettleibig. Die Adipositas ist eine multifaktorielle Erkrankung und führt über ein erhöhtes Risiko für Diabetes, Krebs oder Herz-Kreislauferkrankungen bis hin zu einer deutlichen Herabsetzung der Lebenserwartung. Durch das Versagen konventioneller Therapien wie Diät oder Sport, treten medikamentöse Behandlungsmethoden immer mehr in den Vordergrund. Bisher sind zwei Kategorien etabliert, die Appetitzügler und die Lipasehemmer. Zahlreiche Studien erforschen neuerdings Therapiekonzepte zum Angriff an spezifischen Rezeptoren und Veränderungen des Fett- und Energiestoffwechsels auf molekularer Ebene. Diese Arbeit beschäftigte sich mit der Entwicklung neuer Arzneimittel zur Behandlung von Adipositas in verschiedenen Fettsuchtmodellen an Ratten. Alle Studien begannen mit Vorversuchszeiten von 1-2 Wochen zur Stabilisierung des täglichen Körpergewichtzuwachses, der Futter- und der Wasseraufnahme. Die Tiere erhielten in allen Versuchen eine zucker- und fettreiche Diät, deren Zusammensetzung sich an Ernährungsgewohnheiten in westlichen Industrieländern orientierte (Western Diet). Wasser wurde ad libitum bereitgestellt und die Aufnahme täglich bestimmt. Das gleich galt mit Ausnahme von Versuch 1 auch für das Futter. Am letzten Tag der Experimente erfolgten Blutabnahmen an den zuvor nüchtern gesetzten Ratten. Unmittelbar danach wurden die Tiere in einer CO2-Kammer getötet, die Kadaver einzeln in Gefrierbeutel verpackt und anschließend zusammen mit den Blutproben bis zur weiteren Aufarbeitung gruppenweise bei -20 °C eingefroren. Versuch 1: In Versuch 1 wurde an männlichen Wistarratten eine mögliche Wirkungsverstärkung des selektiven CB1-Antagonisten SLV319 in Kombination mit dem Lipasehemmer Orlistat (Xenical®), auf Körpergewichtsentwicklung, Futter- und Wasseraufnahme, Blutwerte und Zusammensetzung der Tierkörper untersucht. Die Tiere wurden über einen Zeitraum von 4 Wochen einmal täglich mit Vehikel 1 (CMC) oder SLV319 (3 oder 10 mg/kg KG) geschlündelt, und zweimal täglich mit Vehikel 2 (Labrasol) oder Orlistat 50 mg/kg KG. Jeweils nach Gabe von entweder Labrasol oder Orlistat erhielten die Ratten für genau 2,5 Stunden Futter ad libitum. Das Körpergewicht der Tiere war in allen Gruppen im Vergleich zur Kontrolle vermindert: Bei Einzelbehandlung mit SLV319-3 um 50%, mit SLV319-10 um 42% und mit Orlistat um 52%, bei der Kombination tendenziell aber nicht signifikant stärker durch SLV319-3+Orlistat um 76% und durch SLV319-10+Orlistat um 59%. Die Futteraufnahme in Relation zum Körpergewicht wurde im Vergleich zur Kontrolle durch die niedrige und die hohe SLV319-Dosis um 8 bzw. 10% vermindert und durch Orlistat um 18% erhöht. In der Kombination erhöhte sich Futteraufnahme ebenfalls um 11% bzw. 13%. Zusätzlich erniedrigte sowohl SLV319 als auch Orlistat die Triglyzeride, NEFA-Level, das freie Cholesterin, und hatte einen positiven Effekt auf die HDL-Werte im Serum. SLV319 erniedrigte die Insulinspiegel und verbesserte die Insulinsensitivität. In der Carcass-Analyse konnte in allen Gruppen der Körpergewichtsverlust überproportional auf eine Verminderung an Körperfett zurückgeführt werden. SLV319 hat somit ein mögliches Potenzial für die Therapie der Fettleibigkeit, die durch Kombination mit Orlistat noch verstärkt werden könnte. Versuch 2: Die vorliegende Studie erforscht die Auswirkungen von SLV335, einem neuen Carboanhydrasehemmer, auf Körpergewicht, Futter-, Wasseraufnahme und Blutwerte bei weiblichen Wistarratten im Vergleich zu Topiramat. Die Tiere wurden über einen Zeitraum von 4 Wochen zweimal täglich mit Vehikel, SLV335 oder Topiramat geschlündelt. Die Tagesdosen von jeweils 30, 60 oder 100 mg/kg KG wurden zu einem Drittel am Morgen und zu zwei Dritteln am Abend verabreicht. Sowohl SLV335 als auch Topiramat erniedrigten signifikant und dosisabhängig das Körpergewicht der Tiere im Vergleich zur Kontrolle: Bei den drei SLV335-Dosen um 18%, 52% und 85%, bei Topiramat um 38%, 40% und 58%. Auch die Futteraufnahme relativ zum Körpergewicht reduzierte sich, aber nur bei SLV335 um 9%, 15% und 23%, bei allen Topiramat-behandelten Ratten um 11-13%. Topiramat und SLV335 führten unabhängig von der Dosis zu einer Steigerung der Wasseraufnahme, die sich aber nur bei Topiramat signifikant von der Kontrolle unterschied. Weder Topiramat noch SLV335 zeigten signifikante Änderungen der Blutwerte, doch erniedrigten sie leicht die Triglyzeride und NEFA-Werte im Serum. Der CA-Inhibitor SLV335 hatte einen stark gewichtsreduzierenden Effekt. Somit könnte die Hemmung spezifischer Carboanhydrasen ein Mechanismus für Gewichtsverlust sein, und SLV335 ein therapeutisches Potenzial in der Behandlung der Adipositas besitzen. Versuch 3: In diesem Versuch wurden zwei CB1-Antagonisten, das bereits im Handel befindliche Rimonabant (Acomplia®) und die Prüfsubstanz SLV330 in ihren Wirkungen auf Köpergewicht, Futter-, Wasseraufnahme und die Blutwerte bei männlichen Wistarratten verglichen. Die Tiere wurden einmal täglich 2 Wochen lang entweder mit CMC-PEG-Vehikel oder mit 3 oder 10 mg/kg KG SLV330 bzw. Rimonabant i.p. gespritzt. Sowohl SLV330 als auch Rimonabant erniedrigten das Körpergewicht der Ratten im Vergleich zu Kontrolle: Bei der niedrigen und hohen Dosis von SLV330 um 25% und 70%, bei Rimonabant um 37 und 60%. Die Futter- und Wasseraufnahme wurde in allen Gruppen ebenfalls dosisabhängig erniedrigt. Beide Substanzen erniedrigten die Triglyzeride, NEFA und freies Cholesterin im Serum. Lediglich die hohe Rimonabantdosis erhöhte das HDL, verbesserte die Insulinsensitivität und erniedrigte die Insulinspiegel im Serum. Diese Ergebnisse zeigen, dass SLV330 durchaus Potenzial für die Therapie der Adipositas besitzt. Intraperitoneal verabreicht zeigt es vergleichbare Ergebnisse zu Rimonabant. Versuch 4: Die dosisabhängige Wirkung von Topiramat auf Körpergewicht, Futter-, Wasseraufnahme, Blutwerte und Zusammensetzung der Tierkörper wurde an männlichen Zucker-Ratten untersucht, die erstmals mit einer fettreichen „Western Diet“ gefüttert wurden. Die Tiere wurden zweimal täglich über einen Zeitraum von 4 Wochen entweder mit CMC-PEG-Vehikel oder Topiramat (30 oder 100 mg/kg KG) geschlündelt. Das Körpergewicht der Tiere verminderte sich je in der niedrigen und hohen Topiramatdosis im Vergleich zur Kontrolle um 10% bzw. 32%. Auch die Futteraufnahme wurde dosisabhängig unterdrückt. Die Wasseraufnahme steigerte sich dagegen bei der niedrigeren Dosis stärker als bei der hohen Dosis. Unabhängig von der Dosis erhöhte Topiramat im Serum die Triglyzeride, NEFA und LDL und wirkte sich negativ auf das HDL aus. Das gesamte und freie Cholesterin erhöhte sich, die Insulinsensitivität wurde nicht verändert. Die geringe Gewichtsreduktion nach der niedrigen Topiramatdosis konnte fast vollständig auf den Fettverlust zurückgeführt werden, wohingegen die hohe Dosis eine gleichmäßige nicht-spezifische Erniedrigung an Fett, Wasser und etwas weniger an Proteinen bewirkte. Die gewichtsreduzierenden Eigenschaften von Topiramat wurden bestätigt. Vor allem die niedrigere Dosierung von 30 mg/kg führt möglicherweise zu metabolischen Veränderungen, welche eine Verminderung des Körperfetts bewirken.

Hyperthermic intraperitoneal chemotherapy (HIPEC) delivers chemotherapy directly into the abdominal cavity. It is used in conjunction with cancer surgery for people with advanced cancer that has spread inside the abdomen. “Hyperthermic” means warm or hot. “Intraperitoneal” means inside the abdominal cavity, which is encased in a sac called the peritoneum. HIPEC uses high-dose chemotherapy to kill microscopic cancer cells inside the abdominal cavity. The HIPEC procedure is performed immediately after a surgeon has removed all visible cancer in the abdomen. HIPEC is well studied in several types of cancer and being explored as a potential treatment in others. "So really any cancer that's just localized in the abdomen on the surface of the peritoneum could be a candidate," explains Dr. Travis Grotz, a Mayo Clinic surgical oncologist. "We know for sure, based on studies and data that HIPEC works well for cancers of the colon, cancers of the appendix, cancer to the ovaries, cancer of the stomach, and there's even a cancer of the lining of the peritoneum, called mesothelioma. So those would be the cancers I think that are well studied and well accepted. Then, there are more rare tumors that we have less data for, such as cancer to the pancreas or gallbladder or small intestine, that we don't know yet if that's the right treatment."The specific type of chemotherapy used for HIPEC varies depending on the type of cancer being treated. The abdominal cavity is bathed with hot chemotherapy to kill any microscopic cancer cells that might still be present. Heating the chemotherapy enhances its effectiveness because, when it's hot, chemotherapy penetrates the tissue more deeply, increasing the number of cancer cells it can reach.On this Mayo Clinic Q&A podcast, Dr. Grotz explains what HIPEC is, how it is performed, and the risks and benefits of the treatment.Related Articles: "New therapies bring hope for ovarian cancer." "Alternative chemotherapy offers hope for late-stage cancers." "Aggressive treatment turns tide in fighting colon cancer." Advertising Inquiries: https://redcircle.com/brandsPrivacy & Opt-Out: https://redcircle.com/privacy