So, we're going to spend the hour talking about pleural tumors and obviously focusing probably a little bit more on mesothelioma. My role here really in the first few minutes is to go over the classification of different types of pleural tumors. We'll probably really just focus on two in particular, one benign, one malignant. But I'll kind of give you the scheme of what we understand classifications are to start. My name's Colleen Keys. I'm at Mass General in Boston. And then the rest of the afternoon we'll spend going over some of the oncologic treatments and then really spend quite a bit of time talking about surgical management as well with Dr. Chang and Dr. Chin. Great. So when we think about tumors of the pleura, the idea that it was actually a separate primary malignancy is somewhat relatively new in terms of classifying histopathology on the primary tumor of the pleura. Up until the 1960s, people actually believed, pathologists actually believed, that there was absolutely no way that the mesothelial layer of the pleura could arise a primary tumor. So it was assumed till then that they were really secondary tumors that just happened to find themselves in that layer. This physician out of Belfast was actually quite novel in really describing a primary tumor of the pleura. Let's start with benign tumors first of all. The two that you're really going to see most often, and when I say most often, we're talking about solitary fibrous tumors, of all of the malignancies found on the pleura, you're still talking about a very small minority of everything that's abnormal on the pleura you're going to find. So less than 5% of all pleural tumors are going to be this solitary fibrous tumor, but you'll still find it on board exams for certain. They arise actually not from the surface of the mesothelial layer, but it's a submesothelial fibroblast that finds itself proliferating and causing the tumor. A couple of the buzz syndromes that you might see on boards include Pierre-Marie Bamberg, and that's essentially digital clumping and the associated pulmonary osteoarthropathy. The removal of the tumor actually relieves those conditions, interestingly enough. It is thought to arise from a hyaluronic acid secreting tumor. And then Doge-Potter syndrome, which is a tumor secreting ILGF tumor that will lead to hypoglycemia. Most of these will actually be attached to the visceral pleura, interestingly enough. And also interestingly enough, you'll find that some of these can actually be associated with malignant tumors, and they can be quite difficult to discern. But really what the pathologist is focusing on, once they have the biopsies of this pleura, are cases in which you tend to see more necrosis or intratumoral hemorrhage that can give a tip-off that you're actually looking at a malignant solitary fibrous tumor. They'll often use immunostains once you see something that looks quite abnormal in order to distinguish it from a metastatic tumor to the pleura, for example. Some of the other different benign tumors that you might find, I'm not really going to spend a lot of time on those. Because again, if we're talking about solitary fibrous tumors being such a minority, these are really case reports, but they're out there. And then when we talk about malignant pleural tumors, the one obviously we'll be focusing on underneath metastatic tumors to the pleura. This is the most common you'll find of tumors in the pleura. They are typified by epithelioid type, which is really going to be the relative majority of all of the malignant mesotheliomas. And then less frequent would be sarcomatoid. Biphasic has features of both. The grading was recommended initially further back, but there have been some updates in the WHO guidelines in 2021. Most of these are caused by asbestos, but I'm sure there are cases out there where you're not able to elicit that history. So it's certainly not the only causative factor, but certainly a history of some type of asbestos exposure or even sometimes you can elicit the history of a spouse or someone in the family that was washing clothes of someone who was working in an asbestos mine or plumbing for long periods of time, you can sometimes elicit that history. There are a few other types of malignant mesotheliomas. Malignant mesothelioma is considered its own classification. It looks very similar to the diffuse type, but is not thought to spread along the pleura. You can imagine they can be quite difficult to discern and really we're looking at surgical specimens at this point and often entire pleurectomies potentially. And then well-differentiated papillary mesothelial tumors, that's a relatively new classification. It used to be underneath the malignant mesothelioma classification, but has found its own niche in the malignant tumor realm. Small biopsies of the diffuse malignant mesothelioma can sometimes be confused for this type of tumor, so it's important that you have larger biopsies so you don't misdiagnose. And then there are another smattering of much less frequent case report level type tumors, angiosarcomas, other types of tumors that can arise that are also malignant. In challenges for the diagnosis of diffuse malignant mesothelioma, the hyperplasia that's often found in benign conditions can sometimes mimic features. So it's important that you have, in general, larger biopsies. Smaller biopsies can make it a little bit more difficult to diagnose. Same thing, fibrous pleuritis can sometimes be confused as well. You'll often get atypical mesothelial proliferation as a potential diagnosis. You're sort of in that in-between place where, again, it goes back to larger biopsies are really going to help you, in addition to immunohistochemistry. Electron microscopy is used in some centers. Not typically additionally helpful in most cases, and the same with in situ hybridization. Sometimes we'll try to do that from pleural fluid. When I'm really sort of backed up against a wall, it's something we'll sometimes add to see if we could avoid a larger biopsy. Different centers are going to have different experience with the success on being able to diagnose some of these malignant tumors that way. But it could be a potential option in a non-surgical candidate. I want to spend a little bit of time talking about the staging system. I think the history is a little bit interesting in that most of the typing we're really talking about here is all based on large surgical specimens, A. And then, B, a lot of the typing was really based off of all of those epithelioid tumor types. So the stages that they originally were talking about all had to do with where the tumor spread. And really thinking about cases that were sort of, quote, unquote, excuse me, confined to pleural lung pericardium. And then any invasiveness would then increase the stage. And then when you started having distant metastasis, that's where you're at stage four. This is a picture of David Sugarbaker, unfortunately he's no longer with us, but has really left a legacy of driving how we think about these tumors. And oftentimes, the treatment that he really established is very much alive right now. So he started thinking about what influenced the lymph node metastasis really influenced the staging of the tumor. And a lot of their early research brought the point that the spread of lymph node metastasis in mesothelioma, in contrast to the spread of lymph node metastasis in other types of lung tumors, were quite different. And the recommendations that they came up with started influencing their own staging system. And that was subsequently a TNM staging that was adopted by the AJCC, which we still use. And then other groups have used the similar spread of tumor and spread of lymph nodes in adopting their own staging systems. The current system that you'll see most frequently used now is the ISLC guideline, which is using a traditional TNM staging, with the caveat that a lot of those surgical specimens that we talked about are influencing your T staging. And you really essentially need biopsies in order to determine what type of invasion you have. I suppose, if you're looking at something that's fairly confined, that looks fairly superficial compared to something that's very obviously largely invasive into large tumors in the pericardial space, or if there's something contralaterally that you've definitely diagnosed as mesothelioma and not asynchronous primary, you might be able to see that with imaging or other modalities. But this is really predominantly a surgical diagnosis. And then the nodal criteria, this is separating the nodal staging between an N1, where it's fairly localized to the pleural space, ipsilateral pleural space. And then N2 nodes will be, if you look here, N2 nodes would be contralateral mediastinum, ipsilateral contralateral supraclavicular. What was interesting in some of the early nodal drainage studies was that the fact that you can sometimes have a skip in your N1 and can end up with N2 disease without even seeing anything in the N1 nodes. The surgical staging, certainly the patients who were referred for radical procedures, such as extra pleural pneumonectomies, were really not chosen based on their staging grade, but whether they were able to clinically undergo some of those aggressive surgeries. So that could certainly influence the way you're able to stage some of these and kind of build your classifications. The CT chest is often inaccurate in lymph node involvement and diaphragmatic invasion. Like I said, it can be very difficult to really tease that out. And then once you're looking at the difference between the clinical staging, trying to use PET scan, CAT scans, other types of modalities, compared to pathologic staging, the upstaging that occurred with pathologic staging happens very, very, very frequently, up to 80% here in the IA SLC database. This is just pulled from up to date. What I wanted to point out, again, we're still in a realm of cases that are predominantly staged by surgical specimens. The nodal disease we talked about, and then metastasis, the typical category of nothing distant, and then distant metastasis. And that's pretty much where I wanted to end. We'll then talk about, we have next oncology, right? Yeah? All right. All right. Good afternoon. I will be talking today about systemic therapies and potential targeted therapies for predominantly mesothelioma. My name is Angel Chin. I'm an assistant professor at the University of Michigan. And here are my disclosures. So I really want to focus on how an oncologist, I'm a medical oncologist, approaches someone with a newly diagnosed mesothelioma, talk a little bit about our systemic therapy options, and really any new updates with targeted therapies and immunotherapies. So I always like to start with the case. So this is a gentleman I saw in clinic. He's an 82-year-old man. He has a history of hypertension, and he presented with persistent shortness of breath. And this eventually led to some imaging. So here is his CT of the chest. I think that being a medical oncologist, I'm probably the least qualified person in this room to review a CT of the chest. And I always tell my fellows that if I see something wrong, there's definitely something wrong. And as you can all see on the images on the left, there's a plural effusion, but you can also note that there is quite a bit of plural studying all along. So this is screaming some kind of pathology that's ongoing. As one of my residency directors once told me, the tissue is always the issue. It's still the issue. And there's no way that we know what we're dealing with unless we have a biopsy, then talk to our pathology colleagues about exactly what we're dealing with. So this patient underwent a left VATs pleural biopsy, which showed diffused mesothelioma epithelioid type. One of the things I've learned now being attending is that you should always read the extra texts that come with your pathology reports, because it is really important to know how your pathology colleagues actually arrive at this diagnosis. And so here I highlight that this patient's sample was positive for calretinin and D240. These are two mesothelioma markers. They're negative for the other markers. To diagnose mesothelioma, you need actually two positive mesothelioma markers and two negative adenocarcinoma markers, which in this gentleman was the TTF1 and napsin. So as Dr. Keys already gave a wonderful talk on this, I won't review this again, that there are three main histologies of mesothelioma. Asbestos exposure, as she's already stated, is the most common cause. Interestingly enough, the latency period here is 20 to 50 years after exposure. And we still don't really understand what is the trigger that drives the development of malignant mesothelioma after exposure to asbestos. In terms of natural history, epithelioid has the most favorable prognosis. Sarcomatoid is very highly invasive and drug-resistant, and biphasic is a little bit of a combination of both. When I meet someone with a newly diagnosed malignancy, there are, I think, three really important questions I have to answer. And these are what patients want to know as well. One, what is it? And that's where you talk to your pathologist to cinch that diagnosis. Where is it? Have we made all of the appropriate staging procedures? Are there any more procedures that are needed, imaging, et cetera? What is the stage? And ultimately, the prognosis associated with the stage. And then most importantly is something that I think a lot of us forget, but it's really important to know a patient's performance status when you're evaluating them. So is this someone who is fit and active? Is this someone who is already pretty frail? Because that will very much impact their ability to receive any systemic therapy or surgical therapy that you may want to recommend. So this is the patient's PET scan, which was crucial to the staging. And as you can also see, there's a lot of red dots all along the pleura. He was seen by a thoracic surgeon. And despite having an excellent performance status, he was actually deemed not to be a surgical candidate due to the bulk of his disease. So then he was referred to see me. So this is what I have in the medical oncologist as a toolkit. I think it's really easy still for everyone to think that all I have is chemotherapy. Fortunately, in 2022, we have some other new, more innovative, more targeted therapies to offer our patients. With that said, though, cytotoxic chemotherapy is still the backbone of many of our treatments for our cancers. When I think that chemotherapy, I think about drugs that are targeting the cell cycle, DNA repair, mitosis. So these are drugs that are associated with everyone thinking about the typical side effects of chemotherapy, alopecia, myelosuppression, GI upset, neuropathy with some of these drugs. Of course, I think it is impossible to give a talk even at a non-oncology conference without mentioning checkpoint inhibitors. So these are what we call immunotherapy. These are drugs that essentially are disinhibiting the inhibitory pathways on T cells and allowing them to react to the neoantigens on a tumor cell. These are associated with quite a bit of inflammation. I call all of the itis. So unfortunately, we haven't been able to direct our immune system to only go after the tumor antigens. Your immune system can choose to do what it wishes, and it can actually go after normal tissue that's not affected by your malignancy. So commonly seen in the clinic are things like thyroiditis, dermatitis. It's actually fairly easy to manage and doesn't impact future care. More serious immune-related adverse events such as pneumonitis, hepatitis, colitis can actually be much more morbid than the disease itself. We also have tyrosine kinase inhibitors, which are drugs that target specific pathways. These pathways are seen to be constitutively active in malignancies and are thought to be the oncogenic driver of a malignancy. The side effects are very much dependent on which pathway you target. And then we always have other things in development, other small molecules, antibody drug conjugates, and different monoclonal antibodies on specific receptors. For systemic therapy for pleuromesothelioma, though, unfortunately, not much has changed since 2004, with a few caveats. So in 2004, the FDA approved the combination of a platinum chemotherapy, which is carboplatin or cisplatin, in combination with pemetrexa, which is an antifolate. This combination to cytotoxic chemotherapy and is used commonly in lung adenocarcinoma. In lung cancer, which is the bulk of actually what I see in clinic, there's actually evidence to show that you can do maintenance chemo. So after four to six cycles of the platinum pemetrexa doublet, you drop the platinum agent, and you continue with pemetrexa, and that actually shows a progression-free survival benefit. Unfortunately, in mesothelioma, for unknown reasons, there's no strong evidence to actually support the use of continued pemetrexa. It definitely can lead to more toxicities, but doesn't have this clear survival benefit. So it is controversial whether or not you should use it. VEGF, or Vascular Endothelial Growth Factor Receptor, or growth factor that plays a huge role in the pathophysiology of mesothelioma, and we have different drugs that target VEGF. So on the left is a study that combined platinum pemetrexa and imbevacizumab with a VEGF monoclonal antibody, comparing it to cisplatin pemetrexa alone. Here you did see that there was about an almost two and a half month overall survival benefit. The issue with imbevacizumab is that it can cause quite a bit of toxicities, there's actually quite a bit of bleeding, thrombosis, and hypertension associated with this drug, as you can imagine, because it's interfering with vascular endothelial growth factor. And because of the morbidity associated with imbevacizumab, without, you know, not too impressive overall survival benefits. Again, we don't actually routinely use it in the clinic. It does have NCCN designation that you can use it, and in some patients you could, but we don't frequently always recommend it. On the right is another study that looked at the combination of platinum pemetrexin and a drug called nintetanib, which is a TKI, or tyosine kinase inhibitor, actually targets quite a few pathways, but one of them is VEGF. And in this one, actually it was shown that the addition of the VEGF inhibitor led to a decrease in overall survival compared to your platinum doublet chemotherapy, probably because of its toxicities, and so certainly this drug is not approved. What about immunotherapy? So here I will talk about the combination of nivolumab and ipilimumab. Nivolumab, or Nivo as we call it, is a monoclonal antibody against PD-1, and ipilimumab, which is IPI, is a monoclonal antibody against CTLA-4. So if you look at this picture, the T cells in the middle, PD-1 is on the T cell, interacts with PD-L1 on the tumor cell. When this interaction occurs, it leads to an inhibition of the T cell's reaction. And so what happens is essentially the T cell receptor is not recognizing the antigens on the MHC of the tumor cells. So if you go in and block it, either PD-1 or PD-L1, all of a sudden your T cells are allowed to recognize these antigens. Similarly, CTLA-4 is a receptor on your T cell, and it binds to CD80 or CD86 on your APCs. Very similar idea. When you allow this interaction to occur, there's an inhibitory effect. So when you block it, there's a positive effect on the T cells. So this is dual checkpoint inhibition. It's actually something that is used quite commonly in malignant melanoma, and sometimes in non-small cell lung cancer. So this is the CHECKMASE-743 study, which was published last year, that looked at patients with malignant pleuromesothelioma, randomized to the combination of ipinivo versus chemotherapy with a platinum pemetrexid. Here they did show an overall survival benefit of 18.1 versus 14.1 months. And actually, because of an early pre-specified interim analysis, the FDA actually approved this combination in 2020. So this is the first approval in 16 years for malignant mesothelioma. But should it really be our standard of care? I'm not sure yet, and I'll show you why. So on the top, you see the overall survival breakdown based on histology. So for epithelial histology, which is arguably your most common, the survival benefit is numerically better with a combination of ipinivo. However, that is not statistically significant. When you look at the bottom, though, and look at sarcomatoid histology, you see that they're really was a significant benefit of this combination compared to chemotherapy. And so might that positive overall survival benefit really have been driven by the sarcomatoid subtype? Also, immunotherapy can be quite toxic. I think there's this general consensus that it's immunotherapy. It's great. It's easily tolerated, which doesn't give it forever and ever. I actually think as an oncologist, chemotherapy toxicities for me are a lot easier to manage. I know when to expect it. I know what to expect, and I know how to treat it. You stop the drug, and it goes away. With immune-related adverse events, it's very unpredictable. People can have it after one dose, after 10 doses, after you've stopped the therapy six months later. And it can be extremely difficult to reverse in certain situations. And if you look at the breakdown of the toxicities of these studies, you'll see that, not surprisingly, with the combination of ipinevo, you see a lot more diarrhea, pruritus, and rash, hypothyroidism, colitis. And you say, well, this doesn't look terrible, 2% grade 3 colitis. I like to poll the audience, does anybody know what grade 3 colitis is and how much diarrhea you have to have to be grade 3? It's 6 to 10 bowel movements over your daily, and it's enough to put you in the hospital because you cannot stop having diarrhea. So that's grade 3. So it doesn't sound terrible, but it's actually pretty impressive when you look at it. So what's next for mesothelioma? So in non-small cell lung cancer, we actually use the combination of chemo and single-agent immunotherapy quite frequently up front for our stage 4 patients. And so there is an ongoing clinical trial that looks at chemotherapy plus dervalumab, which is an anti-PDL1 inhibitor, versus chemotherapy alone or immunotherapy. And we're definitely looking forward to those results. I was asked to talk a little bit about the medical management of pleural effusions, as this is a common occurrence in our patients with mesothelioma, at least a significant morbidity. And here, really, I feel that it requires a discussion between pulmonary, thoracic surgery, medical oncology. You see, there's a lot of interventions that you can do to really help improve the quality of life. And I think Dr. Chang will probably talk a lot more about that than I can. My point here is that when you look at medical management, you look at the objective response rate to therapies, it's only about 40%. In oncology world, you have to have a very specific percentage of tumor reduction to be considered to have a response. And in my situation, I think to have an improvement from the pleural effusions. The time to response is also not quick. Mesothelioma is not a very sensitive cancer to treatment, and so it can take a couple of months for your therapies to really exert effect. And we think about a patient who is struggling to breathe because of these pleural effusions, I usually don't really count on medical therapies to be the primary management of their pleural effusions. I certainly look towards my interventional colleagues to do something first and cross my fingers that their systemic therapy works. Is there a role for targeted therapy? So this is a pretty cool graph because it shows that in non-small cell lung cancer, there's actually 10 different targeted therapies with multiple treatments in each subgroup, and has really revolutionized the way that we treat stage four non-small cell lung cancer. I will say that in non-small cell lung cancer that has metastasis to the pleura, if they have one of these driver mutations, I actually would feel very comfortable with medical management first because the response rates of some of these drugs are 80 to 90%. So it's, again, really changed the way that we manage non-small cell lung cancer, and potentially a patient can avoid a more invasive procedure. Unfortunately, this does not yet exist for mesothelioma, which speaks to how much more work we have to do in this disease. So just to finish up, the patient, we actually did offer him the DREAMER study. He actually declined and opted for chemotherapy alone. He received one cycle, didn't think he liked it, and so actually pursued alternative therapies in Mexico. He came back to me four months later, and unfortunately on his CT, his disease was stable, and the patient actually opted to do additional chemotherapy for now. You actually can see in some subsets of mesothelioma that have a relatively benign disease course and that you can give them a chemotherapy a couple of rounds, and patients can actually have relatively stable disease even for years. So hopefully this patient will continue to do well off chemo. And that's that. Thank you. We're actually combining Dr. Bueno's talk and my talk just because of some overlap in what we were going to say. So I took some of his slides and my slides, and that's what you're going to hear now. So I changed the title. It's just going to be Surgical Management of Mesothelioma. My name's Stephanie Chang. I am a thoracic surgeon at NYU. And what we're going to talk about today is what are the indications for surgery mesothelioma, what are the different types of surgery, and then what patients get which one, and what are the effects of these overall on survival, as well as adjuvant and neoadjuvant treatment. And then just a very quick slide on future directions for resectable mesothelioma. So in terms of indications for surgery, this right here you can see is a CT scan, and then you can see a PET scan here. This is someone that obviously has extensive disease burden. All these little measurements that they're doing up here is to actually calculate tumor volume because tumor volume has actually been shown to be as important as stage in determining your prognosis after treatment. And here, I know that Dr. Chin had a very impressive PET, but this gentleman also has the bright lights everywhere. So in terms of diagnosis of mesothelioma, you do need to get a surgical specimen. And it does like to see it along the track, so you do try to use a minimal incision to get a surgical biopsy. Unlike almost every other type of cancer, you cannot determine if it is mesothelioma on frozen section. You do actually have to do special stains and wait for it, and wait until final pathology. And then for any patient that walks in with malignant meso, for us, you get the CT, you get a PET scan. The MRI is actually to evaluate exact invasion of your diaphragm, chest wall, and different things like that. And then for most of these patients, we do get an E-bus just to look for a lymph node assessment. The only people that don't get those are the ones that have such advanced disease on imaging. That there's really no point to the E-bus because they're not a surgical candidate. In terms of principles of surgery, what we are aiming for is a complete macroscopic resection of all gross tumor and all of the lymph nodes in that chest. The definition of complete macroscopic resection changes. In the US, you can actually leave one square centimeter of tumor. Generally if that happens, it's because you're doing a pleurectomy decortication on someone that can't tolerate more, and you leave it along the phrenic nerve. But most of the time, all surgeons, we try to remove everything. Surgery is not the end-all be-all for this tumor as well. It always has to be done in a multimodality treatment. Survival is better when it's combined with chemotherapy and then radiation depending on the patient. And then the only other time we do surgery is if they do have local recurrence down the line, then we will consider re-resection if it is systemic spread afterwards and they get systemic treatment. In terms of treatment, there's basically three groups when I think about it. The first is they have limited disease in their ipsilateral chest that's not grossly invading vital organs. The second is the chest disease that's invading the chest wall but is still resectable and or they have positive N2 disease. And then the third is systemic spread and then involvement of the contralateral chest or going through the diaphragm into the abdomen extensively. So for the first group here, we generally do surgery followed by chemotherapy. In group two, which is the more extensive disease, there's two different options. Some people do surgery up front anyways. The standard of practice where I'm from is to do chemotherapy and then restage. And then if there is stable disease or some response and it's still resectable, then you can proceed with surgery. And then group three is just proceed with systemic treatment alone. And then the final role for surgery is, as was just mentioned, that we need to palliate some symptoms. So a lot of these patients have bad malignant effusions that cause trouble breathing and all of the things that you guys see in clinics. So we generally treat them with a pleurex catheter. In terms of surgical options, there's three main surgical options. The first one is a pleurectomy decortication, and this is the least invasive. The pleurectomy is basically removal of the parietal pleura, and the decortication is removal of visceral pleura. The next step up is an extended pleurectomy decortication. So it involves the same from the first surgery, but then you also resect the diaphragm and the pericardium and reconstruct those, and I'll show you all those steps in a minute. And then the last and most invasive one is the extrapleural pneumonectomy. So you basically M-block resect the parietal pleura, the entire lung, the diaphragm, and the pericardium in one giant specimen. And if you are going to be doing this because it is a pneumonectomy, you do need the standard workup with a VQ scan and an echo to roll out any RV dysfunction to make sure they can tolerate it. And again, all these preoperative patients, it's the same type of thing that you would do in a lung cancer pneumonectomy. You'd want to make sure they have the appropriate PFTs afterwards. So in terms of pleurectomy decortication, here you can see the yellow on the outside. That's your parietal pleura, and then this one's your visceral pleura lining the lung. And so this is the pre, and then the post, you can see the only thing that's removed is the pleura there. So the way this is traditionally done is through thoracotomy. So it's a sixth inner space, very large incision, as you can see there on the left. And it is a pretty barbaric procedure. You do actually do what this man is doing, which is stick your hand between the mesothelioma along the parietal surface and the chest wall and stay in that extra pleural plane. And it is a lot of blunt dissection. As you come down, you do peel it again. This is going to be your diaphragm down here. Can you see my... No, this is not working. The pink thing on the left side at the very bottom under your lung is your diaphragm. And so you do just pull it off of that so long as it's not invading your diaphragm. If it is and it's just a small piece, you can do a small resection and primarily repair it. And then the last figure that you can see is the rind of tumor covering the lung. Generally it's not this impressive. Generally it's dotting the lung, and you can just peel it off in certain areas. If you can't peel it off and they won't tolerate a pneumonectomy, you can also just use cautery and burn it, and that will basically destroy the tumor cells. In terms of what this actually looks like on the left-hand side, this is basically a rind of mesothelioma over the lung. And you've cut through it, and you can basically see at the very bottom a peak of the actual lung there. So this is all the visceral pleura that has to come out. And then the important thing in a pleurectomy decortication is this right here, this line. The head is up this direction. The feet are over here. This is your lung. This is your diaphragm right here. And this is your pericardium, and this is your phrenic nerve running around. So the most important thing when you do a pleurectomy decortication is you preserve your phrenic nerve in the function of your diaphragm. So that's the least invasive thing that we can do. The moderate version is the extended pleurectomy decortication. Here again, you can see this tumor. When you resect it all, you actually take out all the visceral and parietal pleura. But then you take a piece of pericardium, and you actually resect the diaphragm. And then because you need something to separate your abdomen from your chest, you actually get a piece of Gore-Tex to reconstruct your diaphragm. And then you get a fenestrated patch for your pericardium. The point of the fenestrations is so that all the fluid can leak out so you don't actually get tamponade. One of the, I guess, updates is we have started doing these things robotically. So here you can see it's a little different than the guy with his hand. So this is actually the chest wall. And then what's getting peeled off right here is the parietal pleura. And so we're starting to peel that off. And that white dot there is a piece of mesothelioma. As we go down, you can see there's more extensive burden down here. This thing's really not the best. Anyway, there's more extensive burden down here that we're taking off. And you don't see it on this, but we do take the entire parietal pleura off. Here you can see some mesothelioma dotting the lungs. So here we're just slowly starting to do a visceral pleurectomy there. And it does result in a lot of air leaks afterwards. And then when we are doing the parietal pleurectomy, we take everything. So we do skeletonize it off of the aorta, off of pretty much everything, because we want all the cells gone. And then for the pericardial resection, again, here's some tumor. You can see there's a little cut here. So behind that is going to be the heart. And so as we go up, this right here is the heart over here. That's actually a coronary artery. This is our pericardial sac. And then here, this white string that we're cutting is actually the phrenic nerve. So it does get dissected in every single extended pleurectomy decortication. And then the last thing that you can do still robotically is you can actually resect the diaphragm. In this case, the gentleman, this is on his left side. So instead of seeing liver here, you actually see preperitoneal fat in that plane. And so you can resect that. In this case, we did a primary repair because not the entire diaphragm was removed. But you can also remove the whole thing and tack it up. And then the traditional surgical management was extrapleural pneumonectomy. And so the way that this happens is it's all M-block. You take everything out. Just like the extended pleurectomy decortication, you are going to take out part of your pericardium and part of your diaphragm. And you're going to have the same reconstruction, but not have the lung there. This is what it looks like through a thoracotomy. So I'm really, this is not, OK. So here is going to be, this is actually open pericardium. There is, I can't see that well, but I think that's your azagus dumping into your SVC. Head is up here. Feet is down here. So this is what it looks like. And that's liver because we're on the right side. And then when it's reconstructed, you can see the pericardial patch. That's the one fenestration they had. And then this is the diaphragm patch. So those are the three major types of surgery. In terms of what are the different outcomes from these, if you look at a meta-analysis, the median survival in surgery actually shows that extended proectomy decortication is as good as EPP. And I would actually argue it's trending towards better. So here you can see for these studies up here, it's actually got improved median survival compared to EPP. The original study that showed this actually had a huge cohort. It was 663 patients in three different centers. And when you look at extended pleural or extra pleural pneumonectomy, which is the dotted line, the mean survival was 12 months, whereas for EPD, the mean survival actually increased to 16 months. One of the main reasons you can see is the actual shape of the curve is the same. But right up here in the very beginning is where all the drop off occurs. And that's pretty much due to the perioperative complications and morbidity of a pneumonectomy. And then if you actually control for stage, histology, gender, and those that received multimodality treatment, the hazard ratio was still 1.4 in terms of dying from EPP. And so these are just multiple studies. For each name, you're going to see proectomy decortication and then EPP. And these are just showing how everything has shifted towards lung conservation in the last 20 years. Here you can see that EPP, the 30-day mortality in all of these studies, is much higher for the pneumonectomy versus the decortication group. If you look at morbidity and complications, same thing. It's just better when you're not taking out the entire lung. And then five-year survival actually does trend towards showing that the pleurectomy decortication patients do better at five years, again, likely due to the complications from surgery itself. In terms of how well can we actually do with surgery, I was pretty surprised when I had first read this. So with extended pleurectomy decortication-based treatment, if you're looking at epithelial mesothelioma, you can actually get to a median survival of three years. So here you can see the progression-free survival is 14 months, and overall survival is 36 months for these patients. And then the most important thing is going to be lymph node status. So on one side, overall survival, you can see if you don't have any N1 or N2 disease and you have a 7.3-year survival, which seems absurd to me, actually, versus 1.9 if you do have lymph nodes. And then the progression-free survival is going to be 2.2 versus 0.8 years. So you can actually have pretty good results, again, with EPD and mesothelioma. And then the question of which operation is best in the setting of neoadjuvant or adjuvant therapy. In terms of neoadjuvant treatment, regardless of the operation, only 50% to 75% of patients that go in for neoadjuvant actually go on to get surgery and complete their treatment. If you do propensity matching of EPP and EPD, there's no difference in time to recurrence or complications. But you can see here that the pleuroctomy decort, which is the dotted line, they still have a better overall survival than the EPP group. And again, it just has to do with the 90-day mortality that comes with EPP. So it's 8% versus 0%. So that, again, is why we have started shifting away from the EPP for these patients. In terms of which operation is tolerated by adjuvant radiation therapy, you can see that there is EPP and then the pleuroctomy decortication. And the ability to tolerate it is actually independent of that. The most important thing is going to be their performance status. So if you have an ASA class III or higher, you are much more likely to not get adjuvant radiation treatment. And then if you're a smoker, you're also much less likely to receive adjuvant radiation. And then in terms of adjuvant chemotherapy, here you can see that the red line is going to be induction. The blue line is going to be post-op. And we're looking at pleuroctomy decortication versus EPP. Both do equally well with post-operative adjuvant therapy. But EPPs do very poorly with induction treatments. You can see that their survival is much less if you plan on doing induction and then EPP. And then to make a very easy thing, so surgery by stage, the stage I'm going by is the T stage. So here, if you look, this box up here, you're going to have the T1A, T1B. And so it's the tumor that's limited to the pleura. And it can or cannot involve the visceral pleura. Both of these can be treated with pleuroctomy decortication and preservation of your phrenic nerve. Once you start invading into the lung parenchyma, you can still actually do a pleuroctomy decortication. But you will do wedge resections of those pieces of lung that are invaded. Once you start involving the diaphragm muscle, then you do have to do either the EPP or EPD, again, just because you have to get all the tumor out. And then if you have a locally advanced but potentially resectable tumor, such as invading your pericardium, same thing. You're going to have to do the extended pleuroctomy decortication or the EPP. And then nodal status, I did just put that up here. If there is N0 or N1, you can proceed straight to surgery. If there's N2 disease, generally not an immediate surgical candidate, you do want to reassess after induction treatment. And then future direction, it's my one slide on immunotherapy and chemotherapy, which I don't ask all the questions to her. But these are the current trials. So there are two major trials looking at induction immunotherapy and its role in resectable mesothelioma. So Dr. Cao is actually doing induction chemo and immunotherapy. So it's neoadjuvant, I can't pronounce it, atizolizumab and cisplatin pemtrexid. So that's a PD-L1 inhibitor. The numbers are very small, again, because mesothelioma is so rare. So 25 of their 28 patients got neoadjuvant treatment. 18 actually got surgery, and only 15 of those received the atizolizumab. And right now, the study results are still pending. And then the other one is, as we just heard, ipinivo has shown some benefit for non-resectable mesothelioma. So Dr. Burt in Texas is now doing induction ipinivo and seeing the effect of that on survival. And resectability. And that's it. Thank you.

pleural tumors

mesothelioma

asbestos exposure

histological types

treatment options

outcomes

clinical trials

multimodality treatment