Good morning, everyone. I'm Anil Vachani from the University of Pennsylvania. It's a pleasure of moderating this session. As you can see now, we're actually at three presentations, so we'll have a little extra time for our presenters and questions if they want it, because I don't think we'll use the whole hour. As the presenters know, you have about eight to ten minutes to make your presentations, and then we'll take some time for questions, and why don't we kick off. So, our first presentation this morning is Dr. Sonokawa, Development of a New Photodynamic Immunotherapy for Intractable Solid Tumors. Thank you. Thank you, Mr. Chairman. I'm deeply honored to be here and present about development of a new photodynamic immunotherapy for intractable solid tumors. My name is Takumi Sonokawa from Nippon Medical School Hospital, Japan. The number of cancer patients is increasing, and cancer is one of the leading causes of death worldwide. Recently, the development of novel therapies, including immune checkpoint inhibitors, has led to significant advance in cancer treatment. However, the therapeutic efficacy is still far from satisfactory, and further development of therapies is still desired. Photodynamic therapy, PDT, is anti-tumor therapy using tumor affinity photosensitizer and low-power laser irradiation, which is minimally invasive, low-cost, and does not impact quality of life, compared with conventional lung cancer treatments, such as surgery or systemic chemotherapy. PDT is approved by Japanese government in Japan, approved for lung cancer and malignant brain tumors, esophageal cancer, stomach cancer, and cervical cancer. PDT has been considered local therapy by itself. However, PDT has been reported to induce not only direct cytotoxic effect, but also enhancement effect on tumor immunity. So, in this study, we investigate the possibility of using the enhancement effect on tumor immunity of PDT to improve the outcome of ICI's for intractable treatment-resistant tumors. This is the work of this study. First, we performed cell viability analysis, in vitro analysis, and next, in vivo experiment. This slide shows the method and the result of cell viability analysis. This is an experiment to confirm the cytotoxic effect of PDT on colon 26 cells. Colon 26 cells, murine colon adenocarcinoma cells, were seeded on 96-well microplate. After overnight incubation, the cells were exposed with tarpolphine sodium and serum-free medium for four hours, followed by irradiated at several light dose. The result, the cell viability rate decreased depending on the laser dose. PDT showed the strong cytotoxic effect on colon 26 cells. This is a method of in vivo experiment for treatment with anti-PD-1 antibody and PDT. Female biopsy mice were randomized into four groups, control, PDT, anti-PD-1 antibody, and combination therapy. After treatment, we measured the tumor size and evaluated the pathological findings of tumor microenvironment. In this study, we used RNP1 for T as an anti-PD-1 antibody. The first, before the experiment for combination therapy, we performed a pre-experiment to determine the optimal laser dose of PDT. Two hours after administration of tarpolphine sodium, the tumor was irradiated by laser at the dose of 0, 30, 60 Joule per centimeter squared. The tumor treated by 30 Joule per centimeter squared showed regrowth after once being reduced in size. So we investigate, in order to investigate the combination therapy, we decide the 30 Joule per centimeter squared was the optimal laser dose. This is a method for in vivo protocol for treatment with anti-PD-1 antibody and PDT. Bulb machine mice were inoculated with colon 26 cells in the right hand flank. The immunological response triggered by PDT might enhance the action of anti-PD-1. So we decide that these protocols, first PDT, and after PDT, anti-PD-1 is administration. This is a result of in vivo experiment for treatment for combination therapy. Compared to control, combination therapy shows the enhancement of anti-tumor effect. It was also found that, sorry, it was also found that the inhibitory effect on tumor growth is observed after a week, a week after administration of anti-PD-1 antibodies. So we investigate the pathological findings after treatment. This is a result of pathological findings of tumor microenvironment. Tumor resected by protocol presented here. This is the CD8 immunostaining findings as shown. The result, CD8 positive cells in tumor treated with combination therapy is significantly higher than that in tumor treated with single therapy or control. Next, this slide shows the IBA1 immunostaining findings. This means macrophage. IBA1 positive area is also significantly higher than that the tumor treated with control or single therapy. Next, this is a PD-L1 expression. PD-L1 expression is also significantly higher than that the single therapy or control. This is a summary of pathological findings of tumor microenvironment. 10 days after PDT, TIL, macrophage, and PD-L1 expression were all increased. On the other hand, 15 days after PDT, TILs were increased, but macrophage and PD-L1 expression tend to increase, but there is no significant statistic difference. These results indicate that the combination therapy was strongly stimulate immunity and enhance the anti-tumor effect. This slide shows the mechanism enhance the anti-tumor effect of combination therapy. According to the several literatures, lack of TILs in tumor is one of the reasons of the failure of PD-L1 inhibitors. In this study, PDT increased the infiltration of TILs into the tumor. Increase of TILs is one of the reasons for improved anti-tumor effect of anti-PD-1 antibody. This slide shows the mechanism behind the increased PD-L1 expression. PD-L1 expression is reported to increase by inflammatory cytokines produced by PD-L1. Increased by inflammatory cytokines produced by lymphocyte or macrophages. These immune cells infiltration into the tumor is increased by PDT or anti-PD-1 antibody. Similarly, radiotherapy is increased PD-L1 expression. So it is effective combination therapy with anti-PD-1 therapy. However, PDT has the advantage is being minimally invasive and is expected to be a convenient combination therapy. This slide shows the optimal timing of PDT and immunotherapy. This is CD8 immunostaining findings after PDT. One day after PDT, TILs were not increased. But 7 days or 10 days after PDT, TILs increased. So in order to get a good treatment efficacy, we saw the treatment strategy. First, photopriming by PDT and several days after PDT, immune cells were infiltrated into the tumor. This timing, administration of PD-1 antibody is performed. We thought it is a good treatment strategy. This is a conclusion. PDT increases immune cells infiltration in the tumor microenvironment. The immunological response triggered by PDT might enhance the action of anti-PD-1 antibody therapy. Thank you very much. Hello everyone. My name is Cosmo. I'm a critical care fellow at Sloan Kettering. First time at CHEST. What a lovely turnout and what a lovely place to have a conference. I'm presenting vascular toxicities of immune checkpoint inhibitor therapies in lung cancer. The results of a nationwide survey. Together with my co-authors, colleagues, Dr. Chisholm, Dr. Kumar, Dr. Thota, and Dr. Pastores. I myself have nothing to disclose. As you all know, immune checkpoint inhibitors have completely revolutionized lung cancer treatment and the treatment of many solid tumors. Representing probably one of the greatest breakthroughs in cancer therapy of this side of the turn of the millennium. In the case of lung cancer, we have a solid five ICIs that are FDA approved. After a number of really fantastic clinical trials. This is just a timeline that you're probably intimately familiar with already. The thing that we were focusing on in this bit of investigation was the toxicities of immune checkpoint inhibitor therapy. Termed, as you know, immune-related adverse events or IRAEs. These are incurred via T-cell dysregulation. Checkpoint inhibitors blockade molecules that mediate the immune system's response to cancer. In so doing, can result in over-activation of the immune system. Not unlike an autoimmune disease. They work in part by down-regulating regulated T-cells and up-regulating affected T-cell expression. Which in turn results in increased cytokine release and humoral mediated anti-tumor effects. And the toxicities incurred by this can affect every organ system in the body. And the frequency of these toxicities and the nature of these toxicities varies by the agent that is being utilized. The regimen, in some cases, the cancer itself. And we really were most interested in arterial and venous thrombotic events in our survey. And these, you know, events have been associated with checkpoint inhibitor regimens. Data assessing these in particular is limited. There's a lot more interest in other sort of groupings of IRAEs. Such as colitis, pneumotoxicity, and so on. But we were interested in the vascular stuff. This is a nice graph displaying the various points of action of CTLA-PD-1, PD-L1 checkpoint inhibitors. And we're looking in this survey at PD-1 and PD-L1 agents. So what we utilized for this survey was a very large data set called the Trinetics Network. The Trinetics Network based in Cambridge, Massachusetts. Specifically the U.S. Collaborative Network which encircles, at the time of this investigation, over 90 million. Currently it's over 100 million patient records. Sort of stripped from across all 50 U.S. states. And these are aggregations of mixed electronic health record data and billing claim data. That have all been packaged together into anonymized patient chart data sets. That can be queried in certain sophisticated ways. Albeit with limitations that pertain to the de-identification of this data. And we were looking at patients diagnosed with lung cancer in the relevant time period. So as to capture patients who are eligible for ICR therapy. Between 2016 and a year before I submitted this, March 2022. And we looked at sub-cohorts who had received FDA-approved checkpoint inhibitors for lung cancer. And we compared them with patients who did not receive these. And we looked at the following outcomes within one year. Of the index event being the diagnosis of lung cancer. These were stroke, heart attack, deep vein thrombus, and pulmonary embolism. With a particular interest in the latter two. We utilized in-platform propensity score matching. Incorporating a wide array of demographic and comorbidity data. So as to try to line the groups up as best we could. And then see excess events. This is just a kitschy graphic on how Trinetics incorporates all the little individual chart and billing data points. Into anonymized patient records that can be collated and strewn about. So there were over 91 million patients at the time of the query. And this 320,000 is the patients with lung cancer within the time period I described before. Not global lung cancer. And we had about 10% or 11% of these received one at least checkpoint inhibitor therapy. And in the gross analysis, this was preceding any propensity score matching. We saw significantly higher incidences of myocardial infarction, deep vein thrombus, and PE with statistical significance. It was about 5.5% versus 4% checkpoint inhibitor versus non-checkpoint inhibitor for myocardial infarction. Small odds ratio of 1.3. DVT 7.5 versus 4%. Odds ratio is about 2 there. And most markedly, PE, it was about 12% versus 5%. Over double the incidence of PE at one year in the ICI group. CVA was not statistically different between... Or actually, I should say, just kissed in the pre-propensity score matching analysis, just grazed into significantly fewer strokes in the checkpoint inhibitor group with a very borderline P value there. And that went away when we did some propensity score matching. This is that propensity score matching. It's a density function. I won't spend any more time on this. The excess vascular events from the checkpoint inhibitor group persisted after we lined our groups up one-to-one with all of those comorbidity and demographic variables I talked about earlier. Slight excess of myocardial infarction events in the checkpoint inhibitor group. 5.6 versus 5. Odds ratio 1.2. DVT and PE rates were still around double. Most markedly, the PE odds ratio was conserved at 2.1. Confidence interval there was 2 to 2.3. No difference whatsoever in CPA incidence. And then we, because we could, went ahead and contrasted PD-1 recipients and PD-L1 recipients and lined them up just as we did those who received ICIs and those who did not earlier. And we saw similar incidence of myocardial infarction. We saw higher rates of stroke in the PD-1 recipients. Odds ratio about 1.2 for that excess 1%. DVT is a bit higher in the PD-1 recipients. 7.6 versus 5.9. And PE was 12 versus 10. It wasn't stratospheric, but it was there. And post-matching we had the same excess after we lined up the patients for their comorbidity data that we were able to line up. Our little survey faced a number of limitations. This database in particular doesn't have incorporated very relevant and interesting things such as cancer staging histology and lines of therapy. Now, the database itself has advanced since March and now has modules that incorporate all of these more granular pieces of data. So we're looking forward to fully plumbing the depths of that for some more granular stuff. And then, you know, more generally, not having access to individual patient level data is a serious limitation to all such database queries. And that, you know, it's sort of a byproduct of regulations that are in effect in the U.S. It allowed us to get this huge N and to get a pretty nice subset of patients overall, but we lose out a bit on the specifics of who was on what medication at what time and how precisely these adverse events we were looking at came about. In conclusion, lung cancer patients had high rates of M.I. and venous thromboembolic disease. We found that there was a persistence of this effect after propensity score matching. And then, you know, we found greater incidence of VTE events in the PD-1 targeting ICR recipients versus those PD-L1 recipients. And this, I think, should make us think that our patients who are on checkpoint inhibitors aren't only at increased risk of single organ system affectations or single organ system involvements like colitis or pneumonitis. They may be in a hyperimmune, hyperinflammatory state like patients who have autoimmune diseases that are at heightened risk of these events. And we should bear that in mind moving forward, perhaps. And that's all I've got for you. Thank you so much. Thank you. All right, guys, let's have some fun. So I'm here to talk to you today about percutaneous perioperative nodule marking in minimally invasive thoracic surgery. My name is Ariana Michaels. I'm a resident physician at the University of North Carolina in the Department of Medicine in Chapel Hill, North Carolina. And I have nothing to disclose. Today, I am going to talk to you about a retrospective review of both marked and unmarked pulmonary nodules conducted at our institution. These nodules were undergoing minimally invasive thoracic surgery. We'll talk a little bit about patient and nodule characteristics as well as surgical and path outcomes. And we'll discuss a little bit about the role of marking in challenging cases. Starting kind of upstream of the problem, let's talk about where this starts. So we are finding increased frequency of long nodule detection both via CTs detected on screening and not screening, so just incidental findings. Not only are we finding increased nodules via CTs just by the numbers, but we're also finding increased detection of smaller, more subsolid pulmonary nodules. And when we find these and they're concerning for lung cancer, we have to talk a little bit about the importance of surgical resection, right? Surgical resection remains the gold standard for definitive diagnosis and often treatment as we're getting better and better at treating lung cancer. As we've shifted in this direction, we're also investigating more minimally invasive surgical techniques because these confer benefits over open thoracotomy, thinking about decreased pain scores, decreased length of stay, decreased risk of bleeding, as well as decreased duration for chest tube post-surgically. And minimally invasive surgical techniques largely encompass video and robotic-assisted thoracoscopic surgery in the operating room. When we think about minimally invasive thoracic surgery, and disclaimer, I'm not a surgeon, but this changes some of the things that our surgeons are able to have that normally happen with thoracotomy, including both visualization and haptic feedback. Haptic feedback changes in video-assisted surgery, but we still retain at least some degree, or our surgeons retain at least some degree because they can insert a finger through the port insertion site for the video-assisted cases and palpate nodules. These are really small, subsolid, or nodules that are very deep to the pleura. Robotic-assisted cases often entails complete loss of haptic feedback. The solution that's been designed to address this is nodule localization or nodule marking. This started years and years ago with hook wire techniques in which a physical wire was inserted via CT or fluoroscopic guidance to resect the targeted nodule. This has advanced over the last few decades and includes now radio tracers, lipid dial, acrylics, as well as microcoils and other fiducial-type markers. That begs the question of who needs nodule marking? When you think about a 20-millimeter nodule that abuts the pleura, that's going to be a lot easier to resect and not necessarily need nodule marking. Whereas a 6-millimeter subsolid nodule that's 15 millimeters deep to the pleura, that might be one where a surgeon requests marking. This has been studied back in 1999. Suzuki et al. reviewed and noted that there was a 63% rate of failed localization for nodules that were more than 5 millimeters from the pleura or less than 10 millimeters in size overall. A study in 2015 reported successful resection went from 48% to 93% of nodules granted under 15 millimeters that were marked with microcoils. To give insight into why nodules are selected for marking, we conducted a comparative analysis of marking versus non-marking to assess whether differences exist in patient, nodule, and surgeon. This review looked at all minimally invasive cases for peripheral pulmonary nodules between May 2016 and December 2021 at a single center. Our primary outcomes included nodule size, consistency, and depth. Our secondary outcomes included patient demographics as well as surgical and pathologic outcomes. A total of 186 cases were marked. The marked cases were split fairly evenly between video and robotic-assisted surgery. The unmarked nodules favor the video-assisted cases. Just a brief word about our nodule marking program. All of our nodule marking is done perioperatively by our interventional pulmonology team via ENB-guided transthoracic needle and logistic regression analysis are listed here. For video-assisted surgery only subsolid nodule consistency was independently predictive of need for perioperative dye marking. For robotic-assisted cases where haptic feedback is especially impaired decreasing nodule size, subsolid consistency, and female gender were all predictive and I'll give you guys a sense of some of the numbers. On average, and these little circles are proportionally sized to these nodules, marked nodules are smaller and typically deeper to the pleura. We have distance from the pleura to both the proximal and the distal nodule reported here in millimeters. More subsolid nodules were marked for both in this analysis. Now that we've established what's associated with dye marking we can review outcomes that are associated with our marked and unmarked nodules. In terms of surgical outcomes there were no differences in length of stay, rate of air leak, localization failure rate, or conversion to open thoracotomy for either robotic or video-assisted cases. For video-assisted cases there was 91% of marked versus 99% of unmarked nodules just sneaking in with a p-value of .05 but otherwise there were no significant differences in terms of diagnostic first resection, margin distance, or first resection mass and on average marking added about 39 minutes for both robotic and video-assisted cases. In conclusion, surgical outcomes were essentially equal across marked and unmarked groups so ultimately the study was not powered to find significant differences for rare events and a prospective trial is needed to help determine what nodules should be marked especially as we move towards more sub-segmental and large wedge resections and I hope the results of this can help inform future studies. Thank you for your attention and coming today. I'm sorry we've had one speaker who didn't show but we appreciate your collaboration and involvement in the hour. Enjoy the rest of the conference.

photodynamic immunotherapy

intractable solid tumors

photodynamic therapy

anti-PD-1 antibody therapy

vascular toxicities

immune checkpoint inhibitor therapies

minimally invasive thoracic surgery