Thanks very much for the kind introduction, and my pleasure to be here in Hawaii, Chess. So I'm going to put forward a few facts and some points with regards to pro towards bronchoscopic ablation. So this is myself, and I work at Prince Wells Hospital, Chinese University of Hong Kong. So the learning lesson objectives really is to let you know a little bit about the role of ablation in our institute and perhaps elsewhere as well, what they're doing, the technique of bronchoscopic ablation for peripheral lesions, and the current data that we have and outcomes relating to this technique, and also one or two slides on future perspective, and to try to persuade you that this may be the future. So if you look at British plastic society guidelines, which may be some of the more conservative guidelines around 2015, if you are not fit for surgery and if you have a image-guided biopsy and you have a malignancy is confirmed, then SABRE or some kind of ablation procedure or local therapy may be appropriate. But then when you look at this guideline as well, and it says that you're not fit for surgery and image-guided biopsy is not possible or you don't get a diagnosis and the nodule is suspicious, you can still deliver this kind of local therapy with agreement from your colleagues, SABRE or ablation. So it's kind of okay to blindly ablate a non-diagnostic or suspicious lung nodule. And this evidence statement is based on the fact that SBRT and also ablation, mostly the data based on RFA, have low rates of acute mortality, although the morbidity is quite variable in terms of the evidence. And the morbidity is, again, based on percutaneous, mostly RFA ablation and energy ablation. But now we have something better. We're going bronchoscopic. We are going using different types of energy. So local therapy choices, taking a step back, there are different choices. One of them is surgery like wedge resection, local therapy like SBRT and also ablation. Traditionally, using percutaneous approach with a high rate of pleural complications, including pneumothorax, fistula formation, and limited access in some areas of the lung. So percutaneous ablation is associated with 11 to 52% risk of pleural-based complications such as pneumothorax or bronchoprofistula. Radiofrequency ablation has a relatively small ablation zone and is less predictable. And it has much less data than SBRT, so therefore it's not very popular in your MDT meetings. But you have to take a step back again and look at SBRT. It actually carries around 22% risk of radiation pneumonitis and pneumonia, and in rare cases can actually cause a mortality as well. But now endobronchally, we have a better approach with much less risk of pleural-based complications and also the energy that we're using is more efficient and more predictable and has a bigger ablation zone such as microwave. When you look at some of the meta-analysis and review articles in the literature, comparing SABR and ablation, for example, this one's from Yale University about two or three years ago, there is a lot more data in SBRT, again, that can be seen there, about 30 times more than ablation. But in this particular well put together meta-analysis, there's no difference in overall survival between ablation and radiation therapy for primary treatment of stage 1 non-small cell lung carcinoma. And another analysis that I was involved in as well, that's recently published, looked at 40 studies that received ablation and 215 studies that received radiation. And again, the conclusion was that there's no difference and there may be a slight advantage for those who receive microwave ablation. So this is what happens with microwave ablation endobronchally. You can see this time-lapse video that if you put that catheter in a tumor, everything dies because you can see the center of the ablation reaches over 100 degrees, it's charred, it's burnt, and there's this cooked area around it that kills tumor cells as well as normal cells. And you can see the very rounded ablation zone there very nicely. So just to go through the procedure in a nutshell very quickly, you navigate using your navigational platform, you use the super-dimensional version 7 to get to your lesion and you confirm with your cone-beam CT. And then you precisely place your catheter, hopefully into the tumor, with fluoroscopic and also cone-beam CT guidance. Once the catheter, as you can see, is inside this tumor, in this case adenocarcinoma, you have a predicted ablation zone, which are these colored circles that you adjust the energy accordingly, and then you do your ablation. And subsequently, you would then confirm that the ablation has taken place and that the margins are adequate with cone-beam CT, and that's the end of your case. So our first publication of our first 30 cases, retrospectively, looking at our data, this was like three years ago, it was just a consecutive number of cases of mean age around 68 years, and the ablation lesion size around 2 centimeters up to 3 centimeters. No intraoperative blood loss, all successfully ablated, and the minimal margin at any area was around 6 millimeters. Some margins were more than 1 centimeter. And the median hospital stay was about one day. So in terms of complications, for our very early experience, we had patients with pain, about 13 percent. 6 percent had a pneumothorax and post-ablation reaction, which is like a low-grade temperature, 6 percent. Mild hemoptysis, that was CTCAE around 2, that just needed monitoring. Infected effusion that needed drainage was one case. Then, more recently, a couple of weeks ago, a NAVABLADE study came out. This is a prospective study that we did together with London, Kelvin Lau's unit, and it's for tumors that have confirmed malignancy, either metastasis or primary lung, not too close to the pleura, and also patients who decline and not candidates for other types of treatment. And in this NAVABLADE study, there were also 30 prospective cases of nodules. Two-thirds were primary lung, one-third were for metastasis, two-thirds in the right and the outer third of the lung, a third of cases in the middle third of the lung. We don't ablate lesions in the center third or near the hyla. Median nodule size, slightly smaller than our initial series of 12 millimeters, and all technically done and mean ablative margin around 9 millimeters. And with one month CT scan showing good coverage, 100 percent coverage. There was one adverse event through to 30 days of a mild hemoptysis, and a couple of subjects had like post-ablation syndrome, again, low grade temperature, some pain, some mild dyspnea that needed oxygen that was weaned off, one hemoptysis that didn't need any treatment, and two pro-refusions. So, just some images to show you. This is an 80-something-year-old gentleman who is not suitable for lung resection, and we ablated this around one centimeter right upper lobe adenocarcinoma. On the right side is the cone beam CT 20 minutes after the ablation showing a good effect and the halo effect that sometimes is seen. And you can definitely see that the tumor is shrunk in size and the margin is about more than one centimeter in this particular case. As we develop our program, we were treating more patients in different categories. This young gentleman had a left pneumonectomy and had a right upper lobe biopsy-proven squamous cell carcinoma about four years later, and the options were limited. He chose this rather than radiation, and we placed a catheter through the tumor near the apex and the medial aspect of the upper lobe on the right side and ablated the tumor. And he's one of our earlier cases in three years, PET-CT shows no recurrence for him. Growing younger still in our vicinity, multifocal lung cancers, plenty of those. A lady who's a mother and also a wife had two tumors resected, right lower lobe lobectomy and also right upper lobe segmentectomy, proven to be multifocal lung cancer molecularly and has two more GGOs of one centimeter on the left side, left upper lobe and left lower lobe. And she chose not to have further surgery and have ablation. So we ablated these two ground glass opacities in the same session. Bigger tumors, we proceeded to doing what's called bracket ablation, where you put the catheter in one side of the tumor and then the catheter on the other side of the tumor to capture a bigger tumor. And you can see on the right side here, the tumor here being covered by the ablation zone. And you can ablate as many times as you want. It's concomitant multiple ablation safe, presented in AATS earlier this year of ablating multiple nodules that we see a lot in terms of metastasis or multifocal lung cancer. And we show that when we ablated lesions that required two or up to four nodules being ablated, we were technically able to do that in one general anesthetic session with a good minimal margin of around six millimeter and the mean hospital stay about just over a day. In terms of complications, ablating multiple nodules did not seem to have a higher complication than ablating single nodule. Although the pneumothorax rate was higher, but when you divide it by the number of nodules that you ablate, it's actually the same. And that makes sense because you're navigating individually to each of the nodules and therefore risking the pleura developing into complication. Operative time much less and anesthetic time much less when you ablate multiple nodules compared to multiple GA sessions. So that's a big advantage for this ablating concomitant nodules. So your GA risks and time saving and the one-stop treatment and cost saving are some of the benefits of ablating multiple nodules. So we've been doing this about four and a half years with a median imaging follow-up around two years. Pneumothorax rate around 4%, effusion rate about 1.7%, infection 3%, and bleeding that was all treated at the first day or in the operation 1.6%. Local recurrence around 7.8%, that's by imaging, of course, very much like SBRT monitoring recurrence, no mortality so far, fortunately. When you look at the SBRT data of radiating tumors of a similar size, up to two centimeters, the one and two year local control rates are 95 and 88%, which is not dissimilar to the data that we have in terms of recurrence. In terms of future, we all know about the lung adenocarcinoma sequence. We're seeing more and more GGOs, perhaps, in our screening programs, smaller lesions detected in earlier stages. And we know that for small tumors, when we do even a wedge resection, which are done a lot in places like mainland China, for example, in these big series, they have 100% survival because a lot of them are in situ carcinoma or very, very early stage adenocarcinomas with very good cellular subtype, for example, epidic and acinic subtypes. And these studies actually show that when you wedge out lesions that are less than one centimeter, even if they have some solid component, they have almost 100% five year survival. So when you look at other types of cancer, for example, colorectal carcinoma, they have a similar adenocarcinoma sequence of development. When you do a colonoscopy, you're taking out the polyps, right, irrespective of whether they are malignant or not. And when you look at the complication rates of therapeutic colonoscopy on the right side, they are not dissimilar to the complication rates on the left side, which is for microwave ablation for lung lesions. So it's just food for thought that whether we, in the future, be able to treat these very early cancers. It's going to get better, of course, with robotic bronchoscopy. And with, for example, Monarch or Galaxy robotic bronchoscopes in terms of ablation, we've done some cases with the Monarch using the new wave catheter. So the last slide, really, the future, there are other ablation technologies that's beyond the scope of this talk, as well as pharmaceutical options for injecting into tumors, et cetera. So I think this area is developing rapidly. And in summary, endobronchial microwave ablation for treating small tumors in select cases is feasible and safe. And this approach really shows that it has less complications, in terms of plural complications at least, than percutaneous approach. We need more high-quality data and longer follow-up. I think that's everyone agrees with that. Robotic bronchoscopy may help us reach these nodules quicker, navigate better, and place the catheter in a better position in the future. And the potential roles in this treatment and screen detect the small tumors in GGOs. So thank you very much. Thank you. We will withhold all questions to the end. So thank you very much. So now it's my pleasure to introduce Dr. Janani Reisenhower from Mayo Clinic. She will take on a different perspective on the bronchoscopic-guided ablation. Thanks, everyone. Good morning. Tough talk to follow, but I'll do my best. For those who don't know me, my name is Janani Reisenhower. I'm a thoracic surgeon and interventional pulmonologist. And I've been tasked with convincing you all that bronchoscopic ablation is not ready for prime time. So as I was thinking about how to propose this argument, the first reference that I should reference is the Merriam-Webster Dictionary, because how do you really define prime time? And if we refer to Merriam-Webster, the first and primary definition is the time period within which the television or radio audience is the largest, the choicest or the busiest time, or the third definition, which is much more in like a colloquial sense, referring to the big time or the big stage. In other words, a pitcher is not yet ready for prime time. So when we talk about bronchoscopic ablation specifically, are we going to encompass the definition that means tried and true, vetted, reliable, such as the networks and television that you see before you, or are we going to talk about clickbait and it gathers the most audience? Apologies for those of you who don't follow sports, but do we follow the definition that generates the most clicks, the most social media, and the most attention? So what do we know about bronchoscopic ablation? I don't want to reiterate all the points that Dr. Ng just made, but I do want to give him credit as the pioneer in this field, as he's put out much of the data that's cited when it comes to bronchoscopic ablation. So this was a prospective two-center, single-arm study, 30 patients, and small tumors using EMN navigation with cone beam CT, as he stated already. There's three endpoints that were defined. They called it technically feasible because in 100% of lesions, the nodules were able to be ablated. They called it safe because no deaths or no pneumothorax in 30 patients. They said it was applicable to primary and secondary tumors because 66% were primary, 33% were secondary, all of which are very reasonable conclusions. And the last statement, the conclusion in the abstract states, transbronchial microwave ablation is an alternative treatment modality for malignant lung nodules less than 30 millimeters in size. Is this the nail that every interventional pulmonologist with a hammer has been searching for? My son would say yes, absolutely. So if bronchoscopic ablation is an alternative, where does it rank among the other alternatives that are currently offered for patients with lung nodules? To answer that question, we have to understand or establish a few key points. What's currently available and what's currently most reported is microwave bronchoscopic ablation. Does that mean that microwave is the best ablative technology, or is there currently the only option for ablation that's out there and well-published? What about long-term recurrence rates? We heard a little bit about the unpublished data, and we'll delve into that a little bit more. Is it applicable to primary tumors, secondary tumors, or both? And does it matter? Lastly, what are the effects that ablation has on the tumor microenvironment? And how does that interplay with combination therapies? As we see trials like the SBRTI trial and the CHECKMATE 816 trial, and we see more and more of a paradigm shift towards multimodal treatment for early-stage disease, even if you're talking surgery, as opposed to nonsurgical treatment algorithms. So let's review the data around these topics and try to answer some of these questions. Much of the data that we have to draw from is from the percutaneous data. And if we look at some of the outcomes across various thermal ablative modalities, microwave, RFA, cryoablation, and then the SOLSTICE paper, which also looked at cryoablation but with a triple freeze protocol, which is bracketing, and a third freeze, which is a slightly different technique than just putting a needle in it and freezing, the local control rates are actually fairly variable, right? 73% in microwave versus 91% in the SOLSTICE trial. The follow-up is also anywhere from 12 to 24 months across all four modalities. We don't really have great five-year data across the spectrum of these different thermal modalities. Lots of patients, lots of tumors, median tumor size is still small. But what about long-term recurrence? And what about specifically in primary lung? Perhaps the best-studied data out there that's prospective data is the RAPTURE study looking at percutaneous RFA following a CT-guided biopsy in 180 or so lesions. This was a mix of primary and secondary disease. And even within the non-small cell group, only 13 of the 33 were stage 1. It's important to note, though, is in those 13 patients at two years, the overall survival was 75%. And the cancer-specific survival is 92%. So that's pretty good. But again, this is 13 patients in RFA. And does that translate across multiple studies, or is this operator-dependent? If we look at the summary of RFA studies out there for stage 1, and a table like this, I will argue, does not necessarily exist for microwave and cryo that's this well-studied. But if you look at PERC data, RFA, five-year survival, it's actually quite poor. It's 22%, 36%. Now, cancer-specific survival in one study is 74% at five years. But it's all over the place. Do you blame the technology? Do you blame the device? Or do you blame the operator? Or is it patient selection? These are all questions that we're still answering, even in the percutaneous world. One last study I want to call out. This is 21 patients with stage 1A specifically, combination of RFA and microwave ablation. This study showed a 48% local progression within a follow-up time of three years. And the median time to long-term progression was 35 months. So again, arguing the point that the data is a little bit all over the place. It does, however, seem to be better in secondary lung. And I think that that's why, in most institutions, percutaneous ablation has had a stronger, more well-defined role in treatment of secondary tumor as opposed to primary tumor. This is a study looking at 40 patients across four sites and 60 metastatic tumors for percutaneous cryoablation. And you can see overall survival rates here is about 50% at five years, which most would say for stage 4 disease is reasonable and is acceptable, with minimal mortality, morbidity, and fairly favorable safety profile. So moving on, what about the tumor microenvironment? Everybody's seen this slide before. This is the cancer immunity slide. We don't need to rehash it. But I think what's important to note is the effect of ICI and the effect that it has on specifically steps 3, 6, and 7 in the cancer immunity cycle, right? Better neoantigen presentation on T cells, better recognition by T cells, and better tumor cell death. And what is the role that ablation has in this tumor microenvironment? We're still early in this phase. We're still understanding this. But the study on the right is a study where PDL tumor progression was actually measured in patients pre and post bronchoscopic vapor ablation in five patients. And what they saw is in about half of the patient population, PDL1 expression was upregulated and increased significantly following vapor ablation. Now is that the properties of the vapor itself, or is it just the properties of tumor disruption? We don't know. We need more studies. But it just goes back into understanding this delicate interplay of what local treatment modality has on the overall tumor microenvironment. And that's what I think will factor into some of these other questions that we've raised, such as long-term recurrence and how to control that better. This has also been shown to be true in pancreatic cancer, shifting gears a little bit. This was a study, a retrospective study, in 85 patients with locally advanced pancreatic cancer. And they looked at treatment with electroporation and chemotherapy, combination treatment versus electroporation alone. And again, this is locally advanced, so patients aren't going to live for years and years and years with this disease. But they did find delayed progression-free survival and longer overall survival with combination therapy as opposed to the standalone electroporation group. Which brings me to the next point. As we start talking about ablation, is the role really in conjunction with multimodal treatment? This is a clinical trial that's open right now for patients that undergo percutaneous post-electric field ablation followed by Checkmate 816-like neoadjuvant chemoimmunotherapy followed by surgery. And this is a patient of mine with stage 2 disease found at the time of diagnosis with that 2 plus centimeter left upper lobe lesion and a positive station 11L lymph node. The patient underwent post-electric field-guided ablation. You can see the placement of the probe. It's fairly close to the pericardium, but the pericardium was completely preserved at the time of surgery. And you can see his pre-surgery image. This is actually pre-initiation of chemoimmunotherapy, and the CT was essentially unchanged after completion of treatment. Ideally, we would like to claim that most of the effect was due to the ablative properties alone. But that's not what's important. What's important is the specimen, and the patient went on to get a thoracoscopic lobectomy and had a complete pathologic response and complete mediastinal and hyaluronic sterilization at the time of surgery. And I don't know if it's easy to tell or not, but that little solid blob right there in the middle of those three critical structures is the scar that was left at the ablation site. Other than some atrial fibrillation, the patient went home without any major issues, without any disruption of the pericardium, as I previously mentioned. And so I bring this slide or this patient or this case up to say that there may be a role for ablation, even in primary lung, but is it standalone or is it in combination? So I'll close by saying that the early data on bronchoscopic ablation is very promising, and much of that credit actually goes to Dr. Ng and his group and the exciting things that they're doing. But we have to remember that it's early. We need to be open, curious, scientific, and innovative. But most importantly, we need to collaborate, because I do firmly believe that this is going to be a multidisciplinary approach and not a standalone approach. And as I tell my children all the time, you need to figure out how to work together and not compete with each other for attention. So in conclusion, yes, ablation is the shiny ball, and it's the thing that everybody is talking about. But is it ready for prime time? And in the words of Coach Prime himself, time is a wonderful storyteller. In other words, time will tell. Thank you. That was wonderful. Okay, so we will bring up our Thank you. So we need to be a little bit careful. I do think there's a role for bronchoscopic ablation. A lot of great rationales for it. For example, the luxury of being able someday to provide diagnosis, staging, and treatment in the same setting is potentially very impactful for patients. I mean, SBRT is, okay, we always kind of throw this as a very easy, and it's outpatient, it's no big deal, but actually it's a big deal to stay laying down for a long time in some box that constrains you. And it's very expensive and not always available in the U.S. We have the luxury of having this available pretty much all the time. That's not the case everywhere. We can also get tissue from molecular analysis, as Janine mentioned, some lung-sparing treatments, an alternative to repeat SBRT for those few patients that cannot get repeat SBRT, for those who have had complications. And then there are a few cases of radio-resistant tumors like sarcoma, renal cancer, et cetera. And it is arguably, most certainly, Now, what are the downsides? Well, we don't have great data on safety, don't have great data on efficacy. We think we're pretty good, but there was just a big debate in the session before that saying that maybe we're not as good as we think in terms of getting to the lesion. I think we've improved dramatically, but we're lacking the randomized data to make that point. And like I said, we don't have a precedent for peripheral therapeutic interventions in the field of IP for treatment of early lung cancer. Now, the FDA regulation of drugs is pretty well structured and makes a lot of sense. You go from discovery to preclinical studies to multicenter randomized clinical trial showing improved patient outcomes. And then the FDA will give you some attention and decide whether or not to approve the drug. And then there's a fairly strict post-market surveillance as well. Now, for medical devices, a bit different. In fact, medical devices have not been regulated for very long. They've been regulated since 1976 with the Medical Device Amendment Act that was passed by Congress under Gerald Ford at the time. And initially, this pathway was supposed to be very similar to that of drugs. So you would have to go through a pathway called the pre-market approval pathway, demonstrate that you have improved patient outcomes, and then the FDA would approve the device. Now, the problem is that there were tons of devices on the market, and people were like, well, what are we going to do with this? So these were grandfathered in, and then they were like, well, we'll probably also need to think of some accessory pathway to allow slight modifications of devices that are not substantially different from the prior device. And for those slight modifications, the 510K clearance pathway was developed and approved. And this is a pathway that essentially allows a device manufacturer to petition the FDA for $20,000 or so, that's the average 510K application, rather than a million-plus dollars for the pre-market approval pathway, and say, look, this is not so different than what we already have on the market. Why don't you just let us commercialize it? It's useful because device companies don't have a ton of money compared to a big pharma, and they have to do that. And if we didn't have this pathway, as I mentioned yesterday, we wouldn't have robots. We wouldn't have cryobiopsy. We wouldn't have a lot of the technology we're using today. The problem, though, is that it's really shifted the responsibility of producing quality data and patient-important outcome data to us. And the problem is that we're not doing the studies. How many randomized control studies do we have in navigational bronchoscopy in the U.S.? We have one, right? And it wasn't great. There are other problems, and, you know, I have to point this out. I'm not very good at juggling big numbers as human beings. When complications are rare, it doesn't make a big difference to us whether you get a 5 per 100,000 deaths or 25 per 100,000 deaths. Between 2008, 2017, there were 2 million injuries and 80,000 deaths from medical devices, most of which were 510K cleared. The definition of substantial equivalence on which is predicated this idea of commercialization without patient outcome data has become the de facto commercialization pathway for devices in the U.S., and that's a big problem, over 90 percent of medical devices. So what do we do? I think the surgery colleagues are a little bit smarter than we are when it comes to that. This is from a group in Australia. The first step is to relabel this innovative stuff as non-validated stuff, and that's just semantic maybe, but it goes a long way in saying that if you don't have data, don't talk about innovation. Innovation carries this positive bias to it, and it sounds cool, and patients like robots and just like they like cars and Teslas and iPhones, right? But as long as we don't have data, it's a non-validated procedure, and non-validated procedures should fall under the purview of an RRB regulatory oversight, and that includes a variety of things like informed consent for the patient and disclosure of conflict of interest and management of conflict of interest, et cetera. The Society of American Gastrointestinal and Endoscopic Surgeons has a nice guideline for new technology and techniques that we should have with NIP. We don't have this, but they're very clear about how things should be done. If you introduce new technology, you're going to have to have good training and good data and preferentially, the training should not be from the company, it should be coming from societies in partnership with the companies, obviously, that's going to be necessary initially. And you need to manage your conflict of interest and do this under the purview of an RRB-approved protocol. So the FDA is really interested, as was pointed out, in bronchoscopic ablation, and last year they had a public workshop that Merman talked at on behalf of the AABIP, I talked on behalf of the ATS, and I was supposed to talk about what kind of evidence we'd like to see. So there's a bit of what I would like to see, but I just want to mention that I've modified the slides a little bit, so this is not official from the American Thoracic Society, this is from me. I think there's three kind of general trial design that we could consider for ablation. One is an ablated risk site that we've just heard about. I think it makes sense as a first step to know what you're doing. Remove the tumor and see what actually happened when you ablated the tumor. Problem with this is that you're not going to have good safety or efficacy data, because you're going to take the cancer out, so everything that happens after that can be blamed on either or, or both. The second design that's possible is the one that is usually the one considered, where you're going to be ablating and then you follow the patient and you look at what the CAT scan looks like. And hopefully at some point you have actual patient important outcome, progression for survival, cancer-specific mortality, et cetera. But for that we typically use the control in terms of what the CAT scan looks like. And that's probably okay as well. The problem is that we have no idea what would have happened otherwise with a different treatment. And so for our community, I think, to embrace this kind of technology and be convinced that this has a role, I think we're going to have to have a comparative study. And until we do that, I don't think we should be doing it, that's my opinion. What should the comparator be? I think SBRT is the obvious candidate, and this should be preferentially targeting patients who are not surgical candidate or decided that they were not interested in surgery. Okay, so I'll go through the PICO type format to go around, go over what I think the patient selection should be, or subject selection should be with intervention, the comparison, and the outcome. I'm not sure about oligometastatic disease, I think that's fine. I think the problem with oligometastatic disease is that if you approve for oligometastatic disease, then off-label use for primary lung cancer will necessarily follow. And so we might as well just study lung cancer, because that's what we're interested in anyway. Patient should be not good candidate for surgery or declined surgery. Informed consent should be standardized. We need to provide the same structured information to everybody. They need to know what they're getting into. We're not telling them this is cryobiopsy versus forceps, that's fine. We're telling them this is how we're going to treat your cancer. We've got this amount of data on surgery, this amount of data on SBRT, and this amount of data on ablation. And we need to be very clear about this. It might be tough to recruit, but studies are hard. We need a central adjudication process, so speaking to the need for multidisciplinary approach to this, completely agree with that. You need an IP person, a thoracic surgeon, radiologist. These cases need to be cherry-picked so that we get the optimal outcomes. Surgeons, I think, should be done by, obviously, experienced people, interventional pulmonologists, thoracic surgeons. You should have a diagnosis. I think ablating without tissue diagnosis for the context of generating quality data that will be compelling enough to influence us and move us to use this technology, we need to have a firm diagnosis, and we need to have full mediastinal staging. One BMCT goes without saying. The comparator should be SBRT, in my opinion. I mean, we're not in the same situation we were, and Mohamed will talk about this. We're in a different world. There's SBRT out there. It's relatively easy, and that should be the comparator. If SBRT is not an indication, that's different, but that's a small, small niche of patients. I would suggest that a non-inferiority study design would be enough to convince us. I think there are true, clear benefits to doing an all-in-one procedure where you get diagnosis, staging, and ablation in the same setting, and much cheaper if we use SBRT. And then the outcome, that remains to be defined. I mean, if you want to look at progression for survival and, you know, complete pathological response and overall survival, that's going to be a complicated study. I'm not even sure we need that. I think if we had a good, standardized definition of local control on imaging, I'd be, personally, I would be happy with that. Secondary endpoints should be all, and should be powered for as secondary endpoints. Just a plug-in for the International Pulmonary Outcomes Group, working on a variety of studies, very interested in ablation as well. I think the field overall is moving in the right direction in collaboration with industry and advanced diagnostic folks, and I think we're hopefully going to be able to generate data that will inform patient care. I think our needs in the clinic should be informing how the technology develops and not the opposite. I work with a lot of engineers and they develop new techniques and then they come to me, where can we use this? I'm like, I don't know. Same thing with ablation. If we have a need, and I think we do, then we should push and we should do the studies. And that's all I have. Thank you. All right, so now it's my pleasure to introduce Dr. Mohamed Wahidi. He's going to tell us a little bit about the experiences from other disciplines and how we can learn from them. Thank you, George. Good morning. What a wonderful session it's been to learn about the pros and cons and how we're going to move forward. So I'm at Northwestern Medicine now, and I want to talk to you about learning from other disciplines. And I wanted to see, how did other disciplines do it, particularly SBRT? So this is my COI. So I went to my radiation oncologist, and I said, how the heck did you do this? Please give me slides, because as we all do, we wait till last week before a test and do the slides. So they gave me slides, but I put my touches on them. But I think the issue here with ablation, bronchoscopic ablation, is the bar is really high, right? Lung cancer survival in stage 1 and 2, as we know, is pretty high, and in main part, due to surgical resection. So if we're going to introduce anything, it is a very high bar. And you want your family member, your friend, to have that same survival in whatever modality they get for treatment. And again, surgery is king. You see all these surgeries. There's a movement now toward less resection, low bar, sparing, if we can get away with less. And there's mounting data that we can probably get away with less tissue resection and have good survivals. But the issue has always been these non-resectable patients, non-operable patients. And if you look at the guidelines, British Psych Society says, all guidelines say you have to have PFT, spirometry, DLCO. BTS says you can't do pneumonectomy if the FEV1 is less than 2 liters. You can't do lobectomy less than 1.5 liters. CHESS wants us to do predicted postoperative pulmonary reserve. And if it's FEV1 and DLCO are less than 60, you really should not do the surgery. So we do have these patients out there that can have surgery. And this is where SBRT came in. I know you all know about SBRT is an external beam radiation therapy, but it's sort of precise. And it's done usually in a shorter time, usually a small number of fraction. It's this sort of finely collimated radiation beams. And it tries to deliver a very accurate high dose of radiation to the target. All right, so the road to building the evidence in SBRT. Well, they start with phase one. Phase one typically is safety. I would argue some of the work that Calvin's doing is phase one, phase two, safety, and then a little bit safety efficacy. So phase one, I want to draw your attention to the references, because I highlighted the years. So this is 2003, the first publication. And in fact, you think SBRT is so well known to us. This article defined what it is. It says, this is a phase one study of a new radiation therapy akin to brain radiosurgery. So people didn't even know about it, that it's being used for the lung. They did 37 patients with T1 or T2, non-small cell lung cancer, biopsy confirmed, N0, M0. They defined medically inoperable, as you can see. And they did three separate fractions over two weeks. Well, again, the focus was safety. So no decline in cardiopulmonary function by symptoms, by O2 requirements. One patient experienced a grade three pneumonitis. One had a grade three hypoxia. Tumor responded to treatment in 87% of the patients. After a median follow-up of 15 months, 60% of the patient experienced local failure. So we do have local failure. But overall, this was good results. And the study said, oh, this is a safe treatment, and we should consider it. So what happened after that? Everybody got so excited, and they all want to do it. And they put it on social media. I think back then, I looked it up. There's only MySpace, and there's no LinkedIn or Facebook. And this is some of what we see today, is we have one study or two, and we're all excited. We're all going to do it tomorrow. And how can we get it to our hospital, and let's do it? But more research reveals more pitfalls. And actually, they did now a phase two study that looked at safety and efficacy. And you can see in this study, they had a lot of grade three to five toxicities, because they treated central tumor. They did not know that treating central tumor can cause that much toxicity. So lessons learned. So you can see this graph on the right-hand side there, where they find where central tumors are, and discovered if you do it there, at least early on, I think we're better now at it. They're much better at it. That there was a problem. There was safety concerns. So if you just went by the first study, you did not know this. This is the second study that showed there's a problem if you don't select the right lesion in the right patient. This is 2006, by the way, three years later. I'm going to show you the time progression and the amount of time it takes to get validated. So what did we learn from early lessons of SBRT? Early encouraging results doesn't always mean that it's the permanent results, right? And that more research needs to be done to discover any unanticipated issues. So phase two trials, more of them were done. And you can see the patients and the work being done. This one, 59 patients. And this one looked better, right? Less toxicity. They avoided central tumors. High rate of local tumor control. Notice that the median follow-up was 34 months, so three years or so. That's pretty good. But wait a minute. This is 2010, by the way. Wait a minute. We follow these patients longer now. We publish the same patients with five-year results in 2018 now. Unfortunately, the great results we saw early on are not as great anymore five years later. Lower overall survival and disease-free survival, more local regional recurrences, and recurrences in untreated locations in the chest, and no significant increase in toxicity. Now, I'm not putting a head-to-head trials comparison to surgery. Surgery has some failure, too. Everything else has failure. But just kind of lessons learned, following the patients up to five years really needed to validate a treatment for lung cancer. And then SBRT, the researchers went to compare it with operable patients now for surgery. And you can see this RTOG0618. Again, phase two, just safety and some efficacy. And they had really good results. Four years, local regional control was 88%. Disease-free survival, 57%. So really good results compared to surgical outcomes. But small study. Again, haven't followed the patients for a long time. And it's not comparative. And unfortunately, when they tried to do randomized control trials of SBRT versus lobectomy, all these studies closed early due to low recruitment. Why? Because we're biased. Physicians are biased. They could not get patients enrolled. The surgeons wanted to operate. Radiation oncologists wanted to radiate. And they could not get those numbers up. And you can see both of them closed early. They tried to do a meta-analysis or combine these, whatever patients were enrolled, 58 patients. And in that small cohort, they showed that actually SBRT may be better than surgery. But this is such a small cohort of patients, not a completed trial, really hard to have any conclusions from these small trials. And as we all know, we now have the VALOR trial, which it took the VA to sponsor to do it. Only the VA system can muster this to say, we're going to do it. We're going to recruit 670 veterans in 21 sites. Again, this is a randomized clinical trial of stage 1 non-small cell lung cancer. Primary outcome is overall survival. Secondary outcomes, FEV1, quality of life, tumor patterns of failure, recurrence, and lung cancer mortality. And the participants are randomly assigned to receive either surgery or radiation treatment. And the VA is doing it well. I think if any of you works in the VA and have that, the physicians themselves are not going to say whether the patient will be randomized or not. Not the surgeon, not the radiation oncologist. There's a really nice way of talking to the patient, enrolling them. And I think this is going to succeed. It is going to take a long time. And finally, because we have data on SBRT, although the controlled trials sort of failed, we had enough evidence over 15 years plus for SBRT now to be included in the guidelines. This is the pathway, right? You do the research, you try to understand it, and at some point you may get included in the guideline. NCCN says SBRT is appropriate if the patient is medically inoperable, patient refuses surgery, high surgical risk, and the primary has to be less than 5 centimeter. And so it made it to the guidelines. So this is sort of a potential path for bronchoscopic ablation. I'm putting random years there. You know, phase one, maybe phase two, Calvin is doing all the work for us, thank you. We need somebody in the U.S. to do it. Again, under IRB, in a research protocol, we cannot be out there, because it's 510-K doing it randomly, because we can't. It has to be a research study, phase one, phase two, maybe, you know, the phase two study in the United States, we get it by 2025, and then finally we get to the randomized control trial, and then maybe, I'm just randomly throwing a number, maybe in 2033 we have inclusion in the guidelines, and some confidence that bronchoscopic ablation is appropriate. Thank you.