Chapters Transcript Video Chordoma with Mass General's Joseph Schwab: UC Davis Orthopaedics Lecture "Chordoma: Continuing Evolution of Care" presented by Joseph H. Schwab, MD, MS including assisting with the World Board examination, President of the scoliosis Research Society and was even called back to active duty in the U. S. Navy during Desert Storm. And so today we honor Den Benson's legacy. His contributions and accomplishments are were significant. And more importantly, Dan was an all around, just a great physician in person. Many of his patients in fact called him dr dan and will come up to him during while he was eating lunch in the cafeteria. So true legacy. A true honor. Um you can see the list of um of invited speakers we've had before and it's a true who's who's list in the world of spine surgery so that I'm gonna welcome joe Schwab and I'm gonna pass the introduction onto the highly high how you're muted. Can you hear me now? Good morning everyone. It is my tremendous honor to introduce Doctor Shop, a good friend and mentor from Mass General Hospital as our guest lecture for the Daniel Benson lectureship this morning. So the swab is a renowned spine tumor surgeon and scholar. Dr Schreiber graduated from Miami University with a B. A. In Religion. He then completed his medical education at Chicago Medical school and with repeated training at the male clinic. He then went on to pursue dual fellowship in spine surgery at the Hospital for Special surgery and orthopedic oncology fellowship at the Memorial Sloan Kettering Center, renowned institute like dr Benson Dr Shroff has dedicated a career toward teaching and scholarly activities. He has published more than 270 peer reviewed publications. His research has really focused toward spine tumor research as well as machine learning to understand and predict clinical outcomes after spine surgery. Dr Shroff currently served as the chief of orthopedic spine surgery at Mass General Hospital. He's the director of psychology as well as the co director of the stefon Harris chordoma Center. On a personal level. I know Dr Schwab because I was resident on his find services PG by four and as a resident on the tumor service as a PG by five Of the 12 is personal. He was compassionate, technically skilled in a very humble gentleman. So with that being said, we're very excited to have at the shop this morning please welcome me in welcoming dr Schwab to U. C. Davis this morning. Yeah, thank you very much. I I um Mhm. Laura and I have gotten to know each other over the years from the A. B. J. S and also time we spent in in Argentina which was great and I've gotten to know eric because his leadership in the AOA and with the Japanese traveling fellowship Hi of course is a is a star and I'm very happy that he's he's ended up at UC Davis under the guidance of erIC and and uh lore I didn't realize there were some other MG. Hs in inn on the faculty which I I see Ellen and brian on there as well which is which is fantastic. A great, great faculty. Um Dr Benson. I didn't realize he had gone to Miami of Ohio. You know, I was actually born in Illinois, grew up in Illinois um and went to Miami as well. So it's that's interesting. But I was a religion major as opposed to an engineering major. Um I'm gonna be speaking about chordoma um trying to share my screen there. I'm not sure you can. Can you see my screen? Okay. Mhm. LLC. There we go. Okay, I'm gonna be speaking about chordoma which is something that that I do care deeply about and has spent a lot of my career studying and caring for patients with this rare disease. Um My my talk is gonna have several small portions a bit about the history of chordoma, particularly with with regard to how it's influenced how we care for patients today. I'll speak about margins because the margins are sort of chased after in chordoma, like an all sarcoma. But I think in particular chordoma and there are there are real consequences for that. Um We'll speak a bit about radiation are our center is known for using radiation particularly in chordoma and and sarcomas and the impact that radiation has had on operative management and how that's affected our surgical planning. Uh I'll then go through some case examples before finishing up discussing some of the research efforts that that our our lab is working on. Um I I think one of the the best centers for for Orthopedics. Um But also for orthopedic oncology is in Gothenburg Sweden um beyond Vinterberg and brutal Stenner of course superstars in the world of orthopedic oncology but also orthopedics in general. And there was a great study on chordoma that came out of there in the 1980s. They had 52 patients uh published in 1981. All the patients were treated with surgery And the surgery was really intra regional surgery. So not unlocks pondel ectomy or say correct to me. And more than half of them have been treated with radiation therapy, two doses less than 50 gray. Um and and one of the things I like about this study is that they have a minimum eight years of follow up which I think is difficult to do anywhere but they can do it in Scandinavia and in Sweden And it's very very important, particularly chordoma because chordoma patients tend to recur and can recur years and years, you know, 10 years, 12 years later they can continue to recur. So minimum follow up is very important. And what this study showed was that only one patient was alive without disease. Um and and this has had a real impact on had an impact on brutal stutter. Um And it also had a big has had a big impact on orthopedic oncology in general because when patients recur in the sacrum eventually and pretty quickly or in the spine it becomes unmanageable. And so patients end up with neurologic compression and loss in the spine there paralyzed in the sacrum, they lose bowel function, bladder function, sexual function. And so and this happens slowly. Uh and and um these patients tend to metastasize late and even when they do metastasize, they can live for years and years, which is a good thing. Um the problem is if they have a fun gating tumor, that's that that is not no longer manageable. They really suffer greatly. And this prompted Bertel Center to to start advocating for unblock spawned elect a me and also for say correct to me this was a big deal. He wasn't the first person to to describe say correct to me, but he really pushed it in chordoma. And this is a, it's hard to imagine a patient comes to your clinic and I see a patient comes in. Maybe they have they have a chordoma that was diagnosed incidentally and now I'm going to tell them, well we're gonna we're gonna take this tumor out and cure you of your disease and you're not gonna be able to have sex with your partner or your you're not gonna be able to control your bowel function or bladder function. Not, not, not a great deal the reason that that people have are offering that to patients is because what people like brutal Stenner experience what happens to patients when the tumor becomes uncontrollable. So what have we learned over the years. Starting with brutal Stenner is that spawned elect a mi se correct me, does actually impact local control and it improves local control that that's sort of a positive. Um And and this has been shown in multiple studies including studies from our own institution. This study happens to be from the A. O. Knowledge for um looking at 100 and 66 patients of chordoma and the mobile spine. And again they found very clearly that that uh on blocks pondel ectomy with negative margins does in fact improve local control. So that's great. The problem is that it may not be the the final answer. This is a nice study out of the Rizzoli Institute, also from Milan. And they they looked at a sort of long term follow up of patients who've had, say correct to me. And what they found was that the patients who've had a negative margin R. R zero resection after 10 years, they had a disease free survival of 56%. So almost 50% local recurrence. Even with an R zero resection, that's a sobering number. And they have a large series. They had followed the patients for a long time and it tells us wait a second. You're we told you we were going to cure you of your disease. We took your bowel function, your bladder function, your sexual function and now the tumor's back, you know, nine years later. That's not not, not so great. Why would that be? Well, there was a nice study out of Japan published a few years ago. Looking at this problem. Looking at what's called, what they called skip metastases. And what they found in chordoma is that in many cases up to 43% of their cases, there are small skip metastases outside of the main mass of the tumor. If you look at this image that I'm showing you here on the lower left, you, this is the margin of the tumor. This is where the main mass of the tumor is. Then you see cancel this bone. You see perry Ostrom and you will see skeletal muscle and within the skeletal muscle. You see these islands of disease. And this is a protein primary setting. And so if I had had a negative margin with bone and and curiosity um around around the tumor, I'd be pretty happy with that. But it turns out I might be leaving microscopic disease here. What they found was that most of these skip metastases are relatively close to the main mass, but they're up to. They can be up to two cm away. And and this was very important. Finding from from my perspective, it helps explain how someone with an R0 resection can many years later have a local recurrence. And it also lends credence to the concept of using radiation in this setting. We we don't believe the radiation works really well in in large tumors. But it does work pretty well in microscopic disease. And so one of the ways that we use radiation at mass general is to deliver radiation outside the main mass of the tumor, three centimeter cuff outside the main mass. And in this case we would be we would be targeting these skip metastases. And we believe this is one of the reasons why radiation does work in this setting. Uh This was borne out in part from from a phase two study published by Tom Delaney, who, who is my co director of the chordoma center here. And they had a very good results. Five and eight year actuarial local control rates of 94% and 85% for for primary tumors. Not quite as good for recurrent for all comers, 81% and 74%. And then sobering number 50%. Local failure in the recurrent group. Even more sobering. All these numbers are now worse. Right. If we follow these patients and we do follow these patients, um none of these results are as good as they were when we first published this paper and in fact in the recurrent group, the local failure rate is got to be 90% or above the good news is that if we have a patient in the primary setting has not had any surgery, we give them preoperative radiation surgery with a negative margin. Follow up with postoperative radiation at that time. We had no local failures. That's no longer true. But the results are are good and I'll go over that. We had the opportunity to look at our series trying to compare whether or not um on block resection is really necessary in in in the case of of chordoma. If radiation really works, why not just do nerve sparing surgery? Why don't we just save these patients sacral nerve roots? Well, it turns out that that in that setting on block resection, it's not terribly surprising, has a better local control rate than interregional. Even a gross total resection combined with radiation therapy. We also found that if you if you give the radiation upfront that tends to have a better chance of local control. This is this is mirroring the data from the prospective randomized studies for extremity sarcoma. Um And and we believe this is because of the microscopic metastases that were able to target in the preoperative setting. But of course this is balanced with higher higher complication rates with preoperative radiation therapy. So our current MGH protocol is to deliver 50.4 grave radiation pre op. This is a proton base but also some photons on block resection with a goal of negative margins followed by 19 point a gray post operatively and in a paper that we're writing up we have 86% local control rate for primary chord omagh's With a median of 7.4 years of follow up and a minimum of five years of follow up so that these numbers are good. I expect these numbers to taper off over time, though, based on the the other data that I just presented to you. The other problem with radiation is it has a has a real impact Um specifically on bone, which is an interest of mine. Um we we have found that that even 50.4 grade radiation induces osteoporosis. It halts or kills the osteoblasts preventing osteoblasts activity. It leads to increased non unions. We have very high rates of non unions with non vascular reconstructions. And then we have 60% insufficiency fractures in the sacrum, even even in the in the nonsurgical patients who elect for radiation alone. So radiation does have a have a real impact on on bone as as we all know. We have a prospective study looking at this but there's a retrospective study that we published where we looked at at, we used hounds field units as a surrogate for bone density. And we compared uh bone outside the radiation field in this case at L. One or L. Two. Um And inside the radiation field in this case would be the sacrum. And so we we uh identified a region of interest in L. One or L. Two. Um And we compared that we compared the preoperative pre radiation levels of the house field unit and that's uh in in those patients versus the preoperative in the sacral spine. Um And then again, compared them after radiation. And what we found was that that in the in the bone outside the radiation field really not much of an impact on the bone. Whereas in the radiation field we had a substantial drop in in uh bone density again, uh suggesting that there is this osteoporosis effect of radiation. This is relatively acute, this is within a few months of the radiation. So here's a case example. This is a 68 year old woman. She presented with a complaint of cough. She really had no pain, it was otherwise healthy. And if you look at her media steinem, she has a widened media steinem here. Um M. R. I demonstrates this lobular mass that's mostly on the bone, but partially in the bone affecting multiple vertebrae. And a biopsy was consistent with with a with a chordoma. And so our plan was to deliver preoperative radiation therapy uh staged resection. And this is a very difficult resection from my perspective because of the location were right behind the heart. It's not going to be easy to get there from an anterior approach. It's it's a little bit risky going posterior only we're gonna try to reconstruct this with a vascular rise draft because of our high rate of non union because of the radiation. And then we're gonna deliver postoperative radiation. We do we do follow a modified on blocks pondel ectomy technique which we described a few years ago In the study we published we had 33 patients. This is really a two stage thread wire saw assisted spawned elect a me. We obtain negative margins in 31 cases we did have to local recurrences and we had one dural tear uh specifically related to thread wire saw passage. And so in this in artist section we we uh this was originally described by Tomita where we we bluntly dissect dorsal to the great vessels. We also do this in the lumbar spine, dorsal to the great vessels, ventral to the the vertebrae. Like you see here we then pass a penrose drain um And and this penrose drain will then serve as a conduit for the passage of our T sauce. And again we do this in the in the lumbar spine and in the lumbar spine it's it's actually um even more difficult because you're sparing the segmental roots and you have the soloist muscle to contend with to say the least about the vena cava and the aorta. So here's the tomato sauce are in place. We take the penrose drain out. You can see we use to t saws and the reason we do that is that they often break and I'll show you a video of that happening. Um And we it is very helpful to have a second t saw available. Um We then passed the T saw dorsal to the vertebrae and ventral to the spinal cord like you see here Um and we secure the tea sauce to the posterior rods. Uh and then we stop. The patient. Is then is then transferred to the recovery room in preparation for stage two. So this is just a short video demonstrating parts of this technique. Again, the the most, most of the time we do follow this this approach. So now we've passed the penrose drains and now I'm passing the T saws through the penrose drain. Um Like it's here, this does make it quite a bit easier. It's much easier to pass a penrose drain in a controlled fashion than the than the T saws. Plus the T sauce can can cut the vessels if you're not careful. So, so having uh having that conduit is helpful. There's a small sheath placed on the T. Saws uh to protect the soft tissues. And now we we uh do our laminate amis and past the T. Saws, ventral to the spinal cord. Um And this next you'll see that we're retracting the lung and you can see the the seesaw is here, ventral to the spinal cord. Um the tea saucers then coiled and sutured to the rods. And the wound is closed in preparation for for stage two. So we all we get a cT scan in between stages and this is to assess the position of our T saws and uh um For planning purposes, we have had a case where we were actually around the as Argus vein. And we found that on the ct scan. So that was very useful to know that before we cut through the a circus and stage two. So we always we always get a CT scan in between stages. Um And then in stage two we we uh released the T. Saws and and cut through the vertebrae. Like you see here in this case, this is the specimen after after resection. Um And we do use vascular sized fibula graphs. We published our experience with this recently um and we use vascular grafts in in uh in the primary and recurrent setting because of our our issues with non union which have been profound. Um And this is just uh schematic showing the the securing of the vascular graft and re anastomosis. We do this with Sandra. Lee is one of our hand surgeons here is quite quite good at this very fast. Um And and then we we, what's not shown here is we do have anterior instrumentation to help compress the the fibula into position. So this is this case, this is the anterior approach and in this case, as I said, it's difficult access. So we had our thoracic surgeons help us. And this is um one of my colleagues chris Morris who's going to perform a stern ah to me in order to access this tumor location. So this is um again, the the position of this tumor is quite challenging and I'll show you the the the reconstruction became more challenging because of its location as well, joe Hey, this is eric are you playing? Are you playing a video right now? I am. Isn't that showing? It's not showing. Yeah, we we don't we see the regular view. Maybe if you can put it into the presentation view would be looking at the wrong screen. Oh, okay. Um How about now? Can you did you see the other video I showed? No, we didn't see the other one. Sorry. Ok. I'm glad you said something. You can go back on the power point and then just do the presenter mode. I was I'm in presenter mode on. It must be it must be latching onto your other screen. Can you see it now? We're seeing the video now. But it's it's not presentable. We're just seeing your Yeah, that's strange because it's in presenter mode on my right screen. I have two screens in my office. Let me um Why? Well, then that show um can you see it. Can I just should I just do it in presenter mode or is that going to be unpleasant? No, If you if you just do it there and press play, we can see it. Okay. That's you can see that. All right. Yeah. Perfect. Alright, fine. So we'll do it. We'll do uh um We'll do it that way then. Low tech. I love it. Thanks, joe. What I wonder. Oh, shoot. Alright. I'll stop pushing buttons. So this is the star anatomy approach. I'm sorry you missed the other, the other screen. But that's okay. I've got some other videos but it's good to know. So this is the stern artemis from chris Morris. As I mentioned, we now uncoil the T. Saws and and use them to to remove the tumor. And you'll you'll this is we're retracting the lung a little bit of the heart as I'm cutting through the vertebrae here. Um avoiding the soft tissues here is obviously tricky. It does require a team average. You can see multiple people helping T sauce really make this much much easier. There's usually just a few soft tissue attachments remaining for delivery of the tumor. What you see here. So it seems easy at that point. But there was I lost a lot of years of life there. And you see the um this is the view of the heart and now in the middle of the screen you can see the the spinal cord which is exposed since we've removed the tumor. Um And the second stage of this is the reconstruction, as I mentioned where we do use vascular grafts. We sometimes will use vascular rib grafts. Um Well, we even used pasteurized tibia graphs in this setting because we're going to use it as a stand alone. We cut this to to uh the size and now we bring it into the field and again we have to place this under, near the underneath the subclavian vessels which you can see towards the middle of your field there. Um And then we gently tap that into position and then we just put an anti kick plate there. Okay. I'm gonna go Hold on 1 2nd here if I could. I'm glad we got to see that video sort of. Yeah. Right. I want to. And the show and I can't bring it over to my other side of the screen, unfortunately. Doggone it. Well, so you guys are looking at my presenter mode I guess. Huh? That's a shame. Alright, well this is the reconstruction, you see. Um Can you see my mouse? Um And I'm demonstrating the the fibula graph that's in position. Okay, fine. Um so that's what this looks like. And uh this patient is now two years out and they have fused up here but the bottom is not fused. And so I'm trying to figure out what I'm gonna do here. So it's not it's not a perfect solution. We have. We did publish this this uh this year we had 39 patients and our union rate was 76% not 100%. Most of our failures have happened in the lumbar spine. And most of those failures have happened because of graph fracture. Apparently not not, I guess terribly surprising. We're asking his fibula to bear the weight of the lumbar spine was probably not a wise choice. And so we we've altered our technique a little bit. Um And this is a case example of that. I sure would like to to make this larger for everybody. I wish I could do that. Um So this is a lumbar chordoma. This is the first case where we started to alter our technique where we place the vascular his fibula graft inside an alley graft. Um And so again this is just the the uh technique where we'll pass the the the penrose drains dorsal to in this case to be in a cave and the aorta and ventral to the lumbar spine. We then pass our T. Saws through the the penrose drain. Um And then this is the end of stage one where we've we've coiled R. T. Saws and if you look closely you can see the T. Saw which is eventual to the fecal sac and the segmental nerve roots. In preparation for stage two where we use a vascular graft. Um And this is just another video showing the the using the T. Saw in this case. Um I was glad I had to seize to T sauce in place because we we did break. You can see that breaking their. And the reason that it breaks is the um We cut on we cut a we were on a screw unfortunately. So that does happen. We used the other T saw and and we're able to then deliver the tumor. Um And in this case we we um we use an al a graph. So in addition to the vascular graft, we we cut an ala graph two size and we hollow out the inside of the femoral Allah graft um in order to to accept the vascular rise fibula. And now you can see the the the vascular fibula inside the AL. A graph with with the the vessels here. Um This is the soas muscle that has a penrose around it. And this is the defect from where the tumor was. Uh And now you can see the the ala graft vasculature fibula graft composite with its vessels attached. And this is the post operative instrumentation. This patient has done very well. He did develop an L. four nerve root injury. The nerve root was intact. But it but it was never it never regained function. He still has some quadricep weakness. He walks with a cane. Um This is another example of uh M. R. I. Of lumbar spine of a patient from a year ago. Um So showing a chordoma. Um There's another video. I'm going to play it on the screen. So you can see it. This is a just an example of the technique where which we use now most commonly. Um And that is the the the ala graft vasculature fibula graft composite. So this is me shaping the the alley graft in order to fit the the vascular photograph without without compressing the vessels. Um And this has obviously been sized. Now I'm cutting out the the area for the the vessels themselves. And again this is done with multiple surgeons. I'm not uh as I mentioned earlier, Sandra lee is one of my partners. And it's really been a huge help from enhanced surgery perspective. Microvascular perspective. Um The the fibula is placed inside the the ala graft uh And again the resize it here uh and then saying is seen cutting the fibula to fit. We then more socialized the remaining fibula that we're not using for for structural purposes. We immortalize it and use it as uh autographed next to the reconstruction. And this is just a schematic showing the insertion of the graft. Mhm. And there's the final reconstruction, postoperative images that you can see. There he is. Now this operation I believe is a year out and he has fused the problem is this is not the end of the story, right. Those those techniques are are have evolved again, we we use the vascular grafts because of the non union rate. We've had lots of complications with that. And we look at are the quality of life after these cases. So we're chasing after negative margins And we we've done a reasonably good job of that I think although again the jury is still out what's gonna happen long term. But what about quality of life if you look at our patients with mobile spine chordoma is the eq five D. Is 50.7 compared to the national average of 0.85. And you know, even even the range of our EQ five D. S is below the national average. Um um We have a high high levels of anxiety in our in our patients are five points higher than the national average, based on the promise anxiety scores and our pain scores are standard deviation above the national average. So these patients don't, it's not certainly not a perfect quality of life by any means, and patients have a primary tumor tend to do better. Um In part, I think because the surgeries are a little bit easier, maybe a little bit more successful and perhaps they're a little bit earlier on in their in their cancer, other cancer fight. Um But what about the sacrum? We know that patients who have say correct to me especially higher, say correct to me or mid say correct to me. You know, they're they're they have varying degrees of function after surgery. And and I tell all my patients when they're going to have a say correct to me, even if we're sparing uh many of the sacral nerve roots, they may not have quote unquote normal function. I don't think that's a word we should be using because I don't think they do have normal function. Uh Some of them have more function than others, but some, many, many patients have no function, right? And and that does affect your quality of life. And so is this really the end of of where we need to be? We're chasing after negative margins um and we're really affecting the patient's quality of life. It's it's to me it's not it's not the end there, there must be something more out there. And so that's one of the reasons why I am interested in in research. Um and so when I first started at Mass General, I had a conversation with you probably can't see this unfortunately, because of the uh the screen, I have to figure that out for my next talk. Um when I first started I had a conversation with Andrew Rosenberg who was the head of of bone bone pathology at the time, and Peter Nielsen and we were talking about this is when immunotherapy started to become uh more interesting to people. This was in 2007 when I started there and and um I started asking about lymphocyte infiltration, chordoma. And Rosenberg had said there really wasn't any lymphocytic infiltrate. So we started to look at it and we realized that they're actually there are lymphocytes in chordoma as and in many cases they can be a profound amount of lymphocytes, it's just something that we're not, we weren't really paying that close attention to. Um and that that really sparked our interest because again, everybody was interested beginning to be interested in immunotherapy? We started thinking well if there are lymphocytes maybe there's an immune response. Um just as a reminder. So what we're talking about here is the interaction between the T cell receptors on site a toxic T. Lymphocytes and the antigen presenting cells. So in this case tumor cells if tumor cells uh the the way that our immune surveillance works are cited toxics T cells will circulate around our body, they'll identify the H. L. A. Class one antigens presenting a protein. They'll identify this as a cancerous cell and kill the cell. That's that's part of the way or one of the ways our bodies um surveys for for tumors so called immune surveillance. Um And and uh my screen just froze which is not good. Okay back on. Um So this is just another schematic of that showing your tumor cell here presenting antigens. You have your T lymphocytes identifying these antigens on H. L. A. Class one proteins on this on the cell surface. They then they then uh target the cell for um for death. And here's an example of what happens over time though these tumor cells tend to escape the immune system by somehow down regulating their H. L. A. Class one expression. So lymphocytes will go right by them and not recognize that these are cancer cells won't really even even see them. And so we started wondering you know what about chordoma sells? You know, how are these cells growing so large are they? Are they that there may be some lymphocytes here? There are some lymphocytes there? What's happening with H. L. A. Class one antigens in chordoma. And so we did a study we published this uh just recently in core looking at 24 Core Domas and we looked at various components of H. L. A. Class one antigens. And we found that 21 of our 24 specimens black components of H. L. A. Class one antigens. And if that's the case that these cells are not going to be able to present antigens to T cells So our T cells won't recognize them. It's one way that chordoma is maybe circumventing our our host response. And so we started becoming more interested in in um in trying to target uh the the tumor cells using a mechanism that does not rely on H. L. A. Class one antigens. And one way to do that is using car T. Um you're probably aware that CAR T. Cells have had really profound success in some cases in so called liquid liquid tumors like leukemia. Some lymphomas but it's not been very effective in solid tumors like Core Domas. Um And 11 of the things that you have to do, you have to identify an antigen on the surface of of your tumors. And in our case we're particularly interested in CS PG four. We've published a few papers showing that chordoma and also Congress sarcoma do express high levels of C. S. P. G. Four. We published a paper a few years ago showing that 72% of our specimen expressed the S. P. G4 on the cell surface. And this is really has limited expression outside of of tumor tissue. And so we decided to to create a car which stands for chimeric antigen receptor directed against the S. P. G. Four. And the way that you do this is that you you take the variable region of an antibody which which can really be modified to target any antigens. And we modify this to target a specific episode on C. S. P. G. Four. And we did this in our lab and in conjunction with a with a collaborator. Um you then expose this to uh adenovirus and then take the adenovirus with the with the car within it and and engineer it into T cells. You take T cells from a patient. You expose it to the adenovirus, you expand the cells and then inject them back into the patient. And the idea then is these T cells are genetically engineered to target specifically the tumor. And again that that you designated in this case. Yes. The S. P. D. Four. Um And what this where this happens This is another schematic. Again this is a car targeted against Cd 19 which is a more common target when when it binds the cD 19 in this case or in our in our example C. S. P. D. Four. Um there there are cascade of events that happen depending on how you designed your car. Um There are multiple different signaling pathways that you can that you can listen. One of the things that that researchers have done, they've identified that car T cells are not working as well in in solid tumors. And so they've designed the endo plastic component of their car to to elicit a larger response by by affecting multiple different signaling pathways a sort of a supercharged T cell. The problem with that is it can lead to a cytokine storm like you're seeing with covid patients and so patients definitely do die with car T. Therapy. And so it is a it's a sort of a risk benefit ratio. You're trying to supercharge your car T. Um without killing the patient in the meantime and that it's still um a lot of ongoing research in this area. But for our purposes we we we are interesting that we've developed this car T against C. S. P. G. Four And another and again and again known as b. seven H. 3. We we also became interested in in um chordoma stem cells or cancer stem cells. So you probably realize that that most you hear about people their cancer is in remission or the cancer has shrunk because of chemotherapy or radiation therapy and then later on the tumor regrowth or comes back and and different theories as to why that happens. One theory is that that you're when you're when you're using a modalities such as chemotherapy or targeted therapy or radiation therapy, you're really killing most of what are called bulk tumor cells. Non cancer stem cells. The cancer stem cells are resistant to those treatments. So the tumor shrinks but don't kill all the cancer stem cells. The cancer stem cells then can regrow and can also form more more bulk disease. And that's why tumor cells recur we did a study in using chordoma cell lines in this case th 22 mug CC one. And we showed that using radiation therapy actually induced the expression of cancer stem cells. Um both A. A. L. D. H. And C. D. 1 33 which are both thought to be markers of cancer stem cells. Um we then quantitative that and we uh quantified that we found that that indeed the bulk tumor cells were shrinking but the the absolute number of cancer stem cells as identified by expression of c. and LDH were increasing. Um And so you know, this again gave an example as to how perhaps chordoma cells are resisting. Um Some radiation also systemic therapy for our purposes. What is also very interesting is that the chordoma stem cells also expressed a high level or a higher level of C. S. P. G. Four. And again, so this lent more credence to the concept of targeting The cells that are expressing c. s. p. G. four with a car t. Um We we did some in vitro experiments and we we found that that indeed the CSP G. Four specific car T cells in combination with ionizing radiation actually had the the the best effect on decreasing tumor volume. And this is an in vitro um as compared to say car T. By itself or radiation by itself. We followed this up in a in a mouse model where the same thing was found that the combination of C. S. P. G. Four car T. Plus radiation had the largest impact on tumor cell growth. Um We we um this was then born out in a luciferase a mouse study where we again compare the the radiation and a C. S. P. G. Four specific car T. Versus other treatments including C. S. P. G. Four car T. Alone. And if you look at the right lower quadrant hopefully you can see this. Um Three out of the five mice had a complete response. Two of the five had had had some remaining disease. Now compare that to the C. S. P. G. Four car T. Also had a nice response but not a complete response. And so there the the combination of these two these two modalities seems to be working reasonably well in in mice. Um And you know obviously at one point we'd love to be able to try to take this to to uh to the clinic. Um So you know in conclusion our evolution of management really really continues to change. So we think that surgery and radiation have improved local control, but that's come at a cost with increased complications, relatively poor quality of life. And and we feel strongly that adjuvant therapies are still needed. Um maybe a car T therapy. There certainly are others that are that are showing promise as well. The current treatment paradigm really shouldn't be the last, I hope that when I when I end my career we're not doing um as aggressive surgery as we're as we're doing right now. Um for the reasons that I that I've illustrated and with that I'll end and and try to take any any questions that that you may have. Thanks so much that I described those incredible body of work. I think dr Randall has one question, joe great to see you virtually. Thanks for spending time with us. It really impressive talk. I I love the fact that we got the the impressive upfront surgery and big picture ticket items well presented to us. I'm sorry about the technical issues. Um and then diving into the science which is always so exciting my my questions for you with your both your in vitro and you're modeling models, did you control for smart B one mutations and deletions because we know that that's heavily involved in in sort of the immuno regulation. And then also if you could wax philosophic about the role potentially of checkpoint inhibitors in a neo adjuvant setting for chordoma as we know that local controls are or challenging. Obviously even with the expert technical team, local relapse is a big issue. So is there any role for some of these checkpoint inhibitors in a neo adjuvant setting to help with local control? So the smart be one we we did not control for. It's a good point. Um We we have not looked at that in in in this setting. Um So I can't really expand upon that further the the with regard to the checkpoint inhibitors. Um I think that in some patients there is a role but the problem is that you know for those to work at your H. L. A. Class one antigens have to be functioning. And so in a subset of our patients they do function but in many of them they don't. And so I think that one of the one of the questions that we're trying to answer is why is it that H. L. A. Is is not being expressed on many of these cancer cells is it because there's a mutation usually not usually it's just a down regulation of H. L. A expression and so can you induce HL expression and then use a checkpoint inhibitor And I think that's a strategy some people are considering and I would be in favor of that. It turns out radiation in low doses does induce HL expression. So it's not it's not HL expression generally it's not mutated it's just down regulated. So if you can up regulate that expression and then combine it with a checkpoint inhibitor I think in the new edge of in setting that would be a good strategy. I believe. Dr leach followed by dr Roberto have two questions. Yes. Uh Good morning Dr Schwab. Thank you for the beautiful lecture. I was fascinated by the car t approach to attack these chordoma. Is are there other cells either locally or regionally that are expressing C. S. P. G. Four that could be detrimentally affected by this strategy? So what we found this far it's interesting that the C. S. P. G. Four tends to be expressed on. Uh So first of all uh interestingly CSP. G. Four in april locks model has been shown to two forms are comas. So so um it's thought to be in a very important um tumor driver in star comas. Ah And and also in chordoma boredom itself. It turns not to be expressed in in non tumor tissues with one exception and that is inactivated parasites. And so um but it turns out that that tends to it tends to be more highly expressed in paris sights of tumors. Um We haven't had significant toxicity in mice both in in uh in terms of healing. So we've done studies looking treating patients with therapies against the spg for not just with party but with monoclonal antibodies and and some other treatments and we haven't found an issue with wound healing um or or major complications targeting CSP G four. But it's a good question. It is a concern of ours. There was a nice study done in a tumor model where they found that the tumor cells did not express C. S. P. G. Four but the activated parasites within the tumor milieu did express the S. P. G. Four and they targeted the CSP G four and the tumor shrank the tumor went away basically. And so it may be that the that the the C. S. P. G. Four targeting is is really effective because of its impact on the blood supply to the tumor. We're not sure which one is more important or if that's variable from one to move to the next. Aargh hi. Can anybody hear me? I'm I'm needed now. So dr thank you for this wonderful lecture on a very very challenging tour. First comment. I mean I think you're being kind of hard on yourself trying to compare uh the EQ five d. results of patients have been treated for a malignant tumor compared to the to the US population in general. I mean probably patients with no people would have much much more lee paul and maybe more fair to compare to treatment for other tumors or smaller groups within these two groups. So I think definitely this is enhancing the life and quality of many patients according to them to the normal populations are very harsh criterion. I just had a technical question about the T. Saw the saw was talking about Tomita and I used to be able to get it for doing midline french parliament applies season and at some point that people from depew told me it was I couldn't get it for that. But where do you get your tea sauce, anterior or ventral or lateral approach? And you have more experience with cutting from poster to answer. And how do you protect the cord? Because there are some japanese surgeons have reported neurological complications and court injuries from from doing the cuts from pulling up towards the cord. So um we medtronic has been producing the T. Sawed if you used to present an animatronic produces the T. So that's what we've been getting it. Getting it from. Um We have more experience from approaching the the spine from an anterior lateral or anterior approach uh cutting away from the spinal cord. I have done cases where we've cut towards the spinal cord and we did um at first we did that with just manual retraction, made me particularly nervous. I then spent some time with uh Stephano biryani in bologna and Alessandro Gasparini and they developed a retractor that actually fits um eventual to the spinal cord and then secures to both of your to either end of your spinal rods and then there's a little slot for the T. Saw. So you're cutting directly towards the chord again. But you have this, this retractor in place. I use that once. Um That's still made me a little bit nervous to be honest with you. Um And and so generally when I when I've done this plenty really I've kind of done a modified approach. I'll have a tea saw that's passed and I'll cut a lot of the vertebrae manually with with a burr. Um And then maybe I'll just cut the very the very end with the T. Saw. Just because for the reasons that you mentioned that we all have this, you know, you wake up at night about complications and that that would be a complication that that I'll probably never go to sleep again. So yes, I've that would make me nervous. Yeah. Yeah. Thank you very much. Hey joe. It's it's eric I've got a question, technical question about the interception of the two graphs. Did you find that you're getting early resort option of your autograph, your vascular autograph? And is that why you needed the alan graf um for structural support? And if so, why not use a cage or something else that might have a better footprint than that? Thin cortical bone. And is it for visualization? Is there some other reason? Well, I think, you know, um we we we went to the alley graph or we talked about cages as well. We went to the alley graph because we were having fractures of the of the fibula, particularly at the cervical lumbar junction and lumbar spine. We had six or 7 cases where the fibula is fractured and and in some cases it the it had healed on both ends and then fractured in the middle and then, but still we didn't, you know, it was not ideal. And so that's why we went to a structural support. Um we chose the autographed. I feel like the holograph actually has a pretty good feel. Our fill of the vertebrae as a, as a wider footprint and a lot of the cages. Uh and you can shape it easier. I just like working with it easier. Um um I don't mind burying it. Whereas I mean, obviously using the cage can do the same thing. But um, I haven't really, I haven't used the cage where I've cut a slot into the cage where the vessels would come out. Um The nice thing about using the telegraph is you can make that relatively smooth. There's no issue of, of, of getting the the the vessels that you know, the segmental vessels or the vessel to be the autographed impinged upon any of the sharp edges that you may cut into the, into the cage. Any other questions dr this is steve thorpe orthopedic oncology as well. It's cool seeing that technique because that's what I've done for ventricular arrhythmias with a pentacle, tibial in the middle. Uh Cool. Seeing the spine. My question is regarding other radiation options. In addition to proton for particle, can you speak to neutron or carbon ion that's been discussed in Japan? I can speak a little bit about carbon ion. Carbon ion is um is attractive because of the properties of the carbon ion in the sense that you have the the similar very similar Bragg peak where you you have an absolute drop off of radiation and essentially no exit dose. And so I think that that's that's attractive. I think also frankly using other other forms of photon radiation is a reasonable approach. I know it's Sloan Kettering. They're doing this very aggressively. Um you know any form of high precision radiation where you can avoid off target effects and therefore increase the dose of the the the biologic effective dose of the radiation that you're delivering. I think it seems to me should be effective. Um I I can't see why protons by themselves are really the way to go. We just have used that here because we have a proton accelerator and it is a way of delivering radiation precisely. But I think with the the advent of I. M. R. T. Uh you know, stereotype radiosurgery mostly based on photon radiation. I would think that that would work pretty well as well. They just have to deal with an exit dose that we don't have to deal with with carbon ions or protons. I have one question for you for big deformity cases? Some centers are combining North surgery and orthopedic surgery to do an attending approach. Are you consistently doing that with Dr SHEn at Mass General Hospital or? So, you know, um I was I really benefited when I came to Mass General uh started working with Fran Hornacek has now has now gone to U. C. L. A. But so he and I worked together a lot. Um and that was great for me frankly. Um I learned a lot from France um and and now I do some cases with john shen dan to Bert is one of our new faculties here and he's very interested in spine tumors. So I work with him but I also work, you know if if kevin Raskin gets a spine tumor, he wants to do it. He'll do it with me. Eric Newman, Santiago Lozano. I actually do cases with lots of different people. I strongly advise doing these cases with another attending. It's it's a it's certainly, I don't know how long I'm gonna live on this earth, but I I think I'll live a little bit longer because I do these cases with other attendings. Um just because it takes a lot of pressure off of you, especially if you're having problems. Um and just the physical and mental load is is just so much easier when you have another attending? I learned that working with Fran and I certainly can continue it. Working with multiple different attendings in neurosurgery but also within my orthopedic colleagues. Okay, any other questions with that being said? I'll leave it to dr klein berg for the last conclusion statement. Well joe I just wanna thank you so much for spending this virtual mourning with us. I am very sad that you could be in person be funded to sit down and pick your brand. And more importantly, we'd love for you to sit and talk with our residents um and uh and uh fellows and get them excited about all the cases that you do and all the things you do we did. We're gonna this plaque is in the mail, as you can imagine uh with the christmas holidays you probably expected in a couple of months. But um we will hope you can place this on your wall and um we really appreciate you spending the time with us and uh and sharing with us your expertise both clinically and um uh scientifically. So thank you so much and I really appreciate it. Thank you so much for having me. It's really an honor. It really is. Thank you. Thank you so much. Dr dr Schwab core curriculum lecture meeting has already started. Do you have the link to get into that one? I think I do. Um I'm going to try to figure out how to get my screen so it works out better this time. So I'll sign out of this one and then and then sign on to that one. How does that sound? That would be great. Margaret magneto's story started it for you. Okay, great. Thanks so much appreciate it. Created by
