Good afternoon, everyone. My name is Donna Shammed. I'm one of the interventional pulmonologists. I will get started since we're running out of time. So I'm going to be discussing a case that we just completed the diagnosis and staging, still in the process of uh initiating therapy. So I think it'll be a good discussion. So this is a 58-year-old woman, history of COPD, hypertension, anxiety, and alcohol abuse who presents after a fall. Patient presents to outside emergency department with mechanical fall and chest wall pain. This is in January of 2025. At that point, she undergoes chest imaging. The CT chest demonstrates a right lower lobe nodule and bilateral chronic rib fractures. The rest of the workup is negative. She's discharged with recommendations for follow-up. She's unfortunately lost to follow-up. So this is the initial uh trauma workup, the PA CT. There's a CT chest, abdomen, pelvis. Uh, there's an 8 millimeter nodule. If you can see, there's a light arrow actually, uh, showing you an 8 millimeter nodule in the right lower lobe round it. Um, in addition to that, they see some chronic rib fractures, no acute injury in the abdomen or pelvis, and no solid organ injury. There's no intracranial hemorrhage. There's some atrophy and some old lagunar infarcts. All right, so moving on, she finally comes back to see primary care in September of 2025. At that time, primary care speaks with her and gets a CT chest. The CT chest now demonstrates a 19 millimeter nodule, and there's a 6 millimeter satellite nodule. She's referred to Fox Chase Interventional Pulmonary. Uh, when I see her in clinic, she has pretty good exercise tolerance. She can walk around, she can do her job. She does have a cough. She uses res 3 for her, uh, bronchodilator therapy, and she continues to smoke about half a pack per day, 20 pack years smoking history. So at that time, a bronchoscopy is scheduled, a PET CT and an MRI brain is also ordered. So this is the current CT scan from September 2025. You can see in the right lower lobe, there's now an enlarged 19 millimeter right lower lobe nodule. You can see immediately adjacent to that nodule is that satellite nodule they're talking about 6 millimeter. You can see it on the axial cuts on the left and the coronal cuts on the right. All right, so she undergoes a bronchoscopy. So the robotic bronchoscopy shows small cell cancer in the right lower lobe nodule. They also performed a number of IHC testing positive for TTF1 synaptophysin, chromogranin, and KI67 is greater than 90%. We also performed lymph node assessment at that time, look at lymph node 11R4R, 11L, and those are all negative and adequate. These are some of the paths. So, on the first slide on the top there, you see the small, classic small blue cells cells. This is a diffcoid stain. This is what we see in the rows in the bronchoscopy suite. So, this is when the cytologist will look at the image and tell us, hey, you have an adequate sample, you can go ahead and collect, uh, at this area. So that's what we end up doing. You can look at some of the IHC testing that is also done. By cytology. So the first one is the thyroid transcription factor stain, TTF1 stain, it stains in thyroid cancer, stains in adenocarcinoma of the lung, and small cells. So now you know not only that the morphology is positive for small cell, but you also have TTF positivity. Additionally, there's a synaptophysin stain on the bottom left. So, this is a neuroendocrine, uh. stain and this is generally done to differentiate between, again, adenocarcinoma and small cell. You don't really know that, need to know that because the morphology is so consistent with small cell, but just to confirm that this is truly a neuroendocrine. Cell origin. And finally, you have the KI 67 stain, which is really a prognostic prognostic score, uh, looking at the proliferation index of these cells, and that was, if you recall, from the last slide greater than 90% and uh it was in fact, uh, pretty high. So, this is a PET scan. Uh, the nodule is lighting up and everything else is negative and the MRI brain is negative. So, I wanted to take this time here to speak with the rest of the panel, kind of discuss what Doctor Edelman was talking about, very limited small cell, and how we would manage this patient. Anybody on the panel want to volunteer to start the discussion? Um, uh, I can. You're on. We recommended that this patient go to surgery, surgery and then systemic therapy. Um, this is a spoiler alert. Uh, I don't know if you know about this part yet. So she, uh, she, she was very overwhelmed. Um, I actually saw her in, um, Marty's clinic, um, so I ran upstairs and saw her, uh, and she was very overwhelmed and she didn't want to meet with surgery, so she's going on to get SBRT. Can you give us some sort of explanation why she would have such a high KI-67 and yet this thing grew barely over a year. I found that really interesting actually. I don't, um, because when I initially looked at the nodule, going from January to September or a period of 8 months, I would have expected this to grow significantly more, be a larger mass, have some lymphadenopathy. I was expecting non-small cell based on the radiographic progression. So I was very surprised to actually see that this came back as small cell. I, I would agree it, it, it's not something you usually see somewhere. Jason. Excellent. Yeah, I think that's the heterogeneity of tumors is that yes there is definitely a small subcomonent here, but it wouldn't make any sense to any of us that this would have just doubled in size in like an 8 or 9 month period of time. So I'm really curious to see obviously she sounds like she's going for another local modality and not surgery. I'd be very curious to see more about what this looked like under the microscope, um. But with a good staging set this sounds really like one of those kind of very limited small cells we all get this occasionally and usually surgery would be how I think most of us would address it but um SPRT certainly does very well and then 4 cycles of vaginine platinum metoposide what I think most of us would go ahead and do, um, so. I would agree, Marty. There are two studies, one from ECOG, one from lung cancer Study Group, uh, where the surgery, chemotherapy were studied, and both negative studies, both ancient history as well. I'm sure they came off the stone tablets. Directly. Any other comments about this case? I. So this person, I don't know, uh, hopefully she can come around and perhaps, uh, see the surgery. I, I realize you've gone ahead with SVRT or at least planning it. I think this is the perfect example of what I call the super limited small cell, uh, which we hardly ever see. Maybe I see once a year, once every other year, um, does have a satellite nodule, so, you know, it's, uh, it's not acting benignly. Uh, the, uh. The surgery, if it's done, obviously needs to be done by a dedicated thoracic surgical oncologist who's familiar with the mediastinum, uh, as Jack has pointed out, uh, small cell can harbor microscopic disease there even though you discovered nothing on the, uh, bronch, but, uh, a full mediastinal assessment is absolutely essential. That ups the ante. If there's, uh, mediastinal involvement, then I would, um, uh, switch gears and probably do a more chemo radiation or I mean you have to radiate the mediastinum. And definitely do an Adriatic, uh, approach. Atezo. No, I know, but, but we don't, uh, she hasn't had surgery yet, so it could be a, I know. So under these circumstances, hopefully you can get her through 4 cycles of at least platinum metoposide. She's young, so theoretically she'd get cysts. I would suspect she won't tolerate that. She sounds very. Uh, medicine averse, she seems to have from what you're describing, low medical literacy. This is gonna be a major challenge to get her through treatment. Uh, Otezo may be a pipe dream, and, and not Otezo, uh, uh, a Dva after, um, chemotherapy may be a pipe dream. Yeah, I think the other problem here is she's already made a clear statement that she's not going to. Go along with the things that you need to do here. I wouldn't give her tarlatab or Burbernac or any of them because, no, no, at, at, at the end of it here, I wouldn't give them to her because I, I don't think she's gonna get regular chemotherapy, uh, well. I have little doubt that Haass or Marty or work hard to get through. Um, going a little bit off of what Jason was saying too about tumor heterogeneity, like this is certainly acting a little unusual for a typical small cell. So I think NGS would actually be very interesting in this patient if you could get it. Um, so I was, so I was done, uh, not for clinical practice, but yes, I would have, I would have done, I usually do NGS for all my small cells in my practice. I, I, I see a lot of small cell. I want to know what the P53 and RB1 status is. Um, I do see these patients, so it's, you know, we, we don't see these, we have not seen these patients a lot, so we don't know what exponential growth looks like when they are from small to moderate, from moderate to big and spreading is what we know from the, from the, you know, the lung cancers. Screening studies and we know that small cell often comes up in interval screening. It's one of the cancers that's highly detected in interval screenings, which tells us that within one year, a lot of things can change with small cell biology when it begins. So yes, I would do NGS just for my purpose, not to drive a lot. I would probably not do immunotherapy based on the dynamics that I saw within one year. I think the radiation is probably going to be sufficient and probably the micromets may be controlled with. Uh, etoposide and cysts, which is not only radio sensitizing, that these doses are, uh, you know, enough doses. They're not like low dose carbotaxol. They, they will prevent micrometastasis from, from what we've learned from older studies. So yes, I would not, and I would not give immunotherapy. I don't think there's any data to back that right now. Would anybody in the room treat this patient differently than with surgery and standard radiation, radiation and or standard chemotherapy? I'm sorry. OK. Doctor Seidman, you wanna give it another try? Do you have the, uh, let me grab. Thanks. It's. So I'm gonna present an interesting case that I think really highlights where we've come and and our options for for treatment of uh advanced non-small cell lung cancer. Um, we saw a, uh, actually amongst the group we saw a 79 year old male who, um, was, uh, referred to us for a new diagnosis of lung adenocarcinoma. Patient actually has a recent history of a stage one renal cell carcinoma diagnosed last year. So we have the luxury of multiple scans that where we've been able to follow things uh preoperatively and postoperatively. The patient had scans done that showed a small right lower lobe lung nodule is about 1.2 centimeters in size, um, that was followed on surveillance imaging, uh, October 2024, uh, January and April of, of this year with stable findings, so it hadn't, hadn't changed in over a year. Uh, over this past summer, the patient presented to the ER with, uh, dizziness and disorientation, had new strokes, uh, he was on rivaroxaban at that time, uh, ended up changing, uh, anticoagulation, um. And right around that time, uh, let me just take a step back, just highlighting some of the other past medical history we mentioned the AFib, uh, heavy tobacco use, um, actually quit in 1979 but at age 30 but smoked three packs a day for 19 years, so. This starting smoking from very early on, um, various industrial exposures, kind of an interesting, uh, occupational, uh, history as well. The medicines, uh, um, one which I highlighted, so he's on a pixaban for the, uh, afib and strokes, but also adrenaro, um, for Afib. He underwent so soon after the strokes he uh um underwent repeat surveillance CT scans and at that time, uh, we did see new mediastinal adenopathy, uh, as well as, uh, the stable right lower lung, uh, nodule. The patient subsequently underwent a PET scan, um, that showed the stable lung nodule but new right supraclavicular, mediastinal, uh, infrahilar and paraesophageal adenopathy, uh, had an MRI brain, uh, that was negative. And, uh, just, just showing a couple of the PET images here, kind of superior mediastinal, uh, mediastinal adenopathy. Uh, subcarinal and then kind of infrahilar all, all lighting up on the PET scan. The first biopsy was actually so the patient needed to be on anticoagulation uninterrupted because of the recent strokes, so he did have an FNA of a right supraclavicular node was positive for adenocarcinoma. The sample was not very good, and they couldn't do further characterization of it, so the patient. It was seen by our group here. It wasn't felt that we had a clear diagnosis yet that, uh, and, and, uh, subsequently need to be bridged with anticoagulation but did undergo an ebus in September, uh, and 4R and 7 were positive for adenocarcinoma, uh, consistent with a lung primary. We sent off our in-house, uh, NGS panel, uh, looking at DNA and RNA and kind of got some interesting results back. So the PDL1 was 70%. Uh, there was a BRAF, uh, V600E mutation and on IHC MT was 3+, uh, also P53 positive, uh, negative for ALC metT or HEER2. Uh, um, patient was presented at our tumor board conference, uh, initially with a recommendation, uh, for chemo radiation followed by con concur, uh, maintenance dervalumab per Pacific, um, if, uh, it was felt that the, uh, uh, if the patient was, uh, uh, amenable or the disease was amenable to radiation, so we saw a radiation oncologist and there was a recommendation for chemo radiation. Because of delays with anticoagulation and he sought a second opinion with us when he was simulated for radiation, it did look like there was some disease progression, so a new pleural effusion, some lymphangitic spread of cancer, so you potentially kind of missed that window of considering radiation. And the patient was represented at our tumor board and with that progression it was felt that we should start on systemic therapy, uh, first, that this would be a wide, uh, area to, to radiate a possible, uh, uh, pleural fusion and too small to tap, but, but that radiation might be too extensive here. So the recommendation at that point was to, uh, initiate systemic therapy and with that, uh, you know, reviewing the molecular data once again, the PDL1 of 70%. BRAF V600E mutation and met IHC 3+. Uh, what, what do we do here, um, and I just outlined some of the approaches based on the, on the targets that we have and some of the studies, but, uh, curious to open up to the group on, on what you would do here. So I think the PDL1 greater than 50% certainly has some advantage because uh patient does not have an AC or an EGFR mutation. I usually would start with um platinum, um, pemitrexate and, uh, an IO therapy for this particular patient. I see there will be some other things available in the 2nd and 3rd lines, but I typically would start with, uh. Platinum, Alimta and uh for example Keytruda first line. I don't know if you wanna Yeah, I, I agree with that. And the, the patient is, uh, how old again, Mike? Uh, 79, OK. And is he pretty good performance status or residual deficits, but still, you know, functional, OK, yeah, so I would definitely start with, with chemo Keytruda, but then have a pretty low threshold if we run into issues with the chemo to just kind of ride on the Keytruda as long as we can. Awesome Yeah, yeah, great case. Uh, first of all, that occupational, you know, history, you know, damage control school, uh, you said that that's unique. Uh, I mean, I thought that's medicine residency, damage control school. I mean, all of us did that, but anyways, uh, kidding aside, uh, fascinating case, and I think it's a situation of equipoison medicine currently, and I think that's both Mtexon 14 and BRAF that we actually do not know whether targeted or immunotherapy-based treatment choice is the best front line. Just the last couple of weeks there were actually some very nice um collaborative studies, you know, presented on both and published on both, uh, and there seems to be maybe some, some characteristics of the TPS called really high positive patients where maybe IO is potentially superior than than targeted therapy, but in all honesty we don't know. So I think it's appropriate to. Present both to patients targeted therapy, very rapid response, so that that's intriguing for a patient who's rapidly progressing. At the same time, immunotherapy, you have the potential for the long term benefit, but either way, you have two great, you know, potential frontline choices. I chemo, I similarly kind of borderline. I, I, I do have a question here. So, you know, usually when we commit somebody to immunotherapy. And then we have to give tyrosine kinase inhibitors. At least the data from the EGFR directed TKIs is that, you know, the, the, the, the closer we keep them together, we may see higher risks of immune-related adverse events. I don't know if there's any data with, um, the BRAF inhibitors with that, since we, if we commit the patient to immunotherapy, they have a long half-life. Uh, and then we would be poised to use targeted therapy in second line before going to teleovi or or something like that for this person. So I'm, I'm sort of just curious to know the thoughts there. We have not seen that with the BRAF. Our melanoma colleagues have done the sequencing back and forth, back and forth, so I think the safety is OK, and the melanoma trials highlight immunotherapy better, but melanoma is a different disease than lung cancer. But I do want to bring up that that asthma, we have the updated data for the Pharaoh studies, and median survival was around 45 months with that combination, I mean. It's, it's a pretty amazing results we're getting with the targeted therapy in this case too. It is stunning. I have to say though that there's a trial with a PFS of like 12 months, you know, for the, for the same combo, so you don't know where the truth is, maybe somewhere in between, but definitely good choices. I would, uh, I mean, you're assuming this patient is metastatic, probably is, but I would have tapped the fluid, make sure that there is metastatic disease there. I probably still end up giving systemic therapy even if I wasn't 100% sure. Lymphaitic disease, I don't, you know, that could be post obstructive changes. It could, uh, it might merit a repeat, uh, Bronck, but assuming this is all, uh, now stage 4, which we all suspect, um, I would have equipoise actually doing a study comparing the, uh, uh, the doublet, the TKI doublet to, uh. Standard, uh, IO based, uh, therapy, I think there's enough data either way, um, that 4 year, uh, you're right, in the second line, uh, the these combinations don't seem to be so great, but the, the 4 year data, it was Melissa Johnson, right, that presented, it was, uh, I mean, it's right up there with, uh, EGFR now when you think about it, uh, in terms of median survival, uh, so I, I think you could be justified either way. Uh, and obviously one would be backup if, uh, um, the patients has progression which unfortunately is most likely. I've had patients like this who got the, um, the doublets, some of them have had amazing, um, long term survival, uh, peculiarly every single one of my patients with BRAF has had pleural effusions. I don't know if that's something that. Uh, uh, as unique or just, uh, anecdotal, uh, I am currently, uh, salvaging one of these patients with, uh, keynote 189, and she's had a durable response to that. So like many of these other individuals, they can go on for quite a while. Just want to share a heavy smoking history, yeah, yeah, yeah, smoking history too, um, ASCO does publish, they call them living guidelines I guess that are updated frequently and, uh, with the highlight unfortunately didn't project very well, um, but showing that that BRAF inhibition, uh, is a considered option here, uh, low uh low level of, uh, quality evidence but a high strength of recommendation. And, uh, uh, here and then in looking at, um, NCCN guidelines also, you know, for, for, for kind of how we, how we treat patients, uh, um, you know, for the PDL1, uh, uh, patients, it's mentioning negative actionable mutations above. So I, I, I think some of that kind of swayed our judgment. Um, if one other part of the history I didn't share is that the patient has a severe needle phobia, uh, and, and so these. The these options uh were discussed and, um, after the discussion we, uh, um, decided on, uh, uh, uh rafenib and tremettinib. Um, there was a drug drug interaction, uh, with jornaarones so that led us to, to that, uh, BRAF, uh, doublet, uh, for this patient. great? Uh, any role for consolidated radiation in a, a BRAF targeted patient, uh, um, after a couple months. Response is, oh, sorry. Oh, it's on. Um, I know there is some limited data, um, for these BRAF patients after they've gotten the targeted agent, and I just think we have to see what the, what the response is and then make that decision if it's a really good response with a little bit of residual disease, sure. All right. I'd like to thank all of you for participating. Uh, it's time, um.
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