The Clinical Implications of the Genomics of Meningiomas

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- Colleagues and friends, thank you for joining us for another session of the virtual operating room. Today we have special guest, Dr. Jennifer Moliterno from Yale Neurosurgery. I'm really honored to have Jennifer with us. I've been following her career at many levels since she was a resident at Yale, where I did my neurosurgery fellowship although she started after my time. She's much younger than me, as you can imagine. And really her meteoric rise in neurosurgery as skull base and complex neurosurgery is truly, truly amazing, admirable. She has become the chief of neurosurgical oncology at Yale Neurosurgery. I follow her on Instagram and social media and her professional presentation of her cases are second to none. The kind of caliber of cases she tackles are incredible. Her technical skills are really something that I wish I could see more often among our young neurosurgeons. Jennifer, it's really truly admirable and I can only be sure that your successes will be more and more, and I'll witness many more of them in the future in academic neurosurgery. You have been an incredible role model for many young neurosurgeons and my sincere congratulation on that. So today you're gonna talk about the genetics of meningiomas. You're gonna hopefully give us some of your technical pearls as well. And I'm very excited to learn from you. Please go ahead.

- Thank you so much. Thank you for your kind words and thank you so much for having me. It's really an honor to be here. So I'm gonna talk about the clinical implications of the genomics and meningiomas and of course, knowing and respecting that this is the neurosurgical atlas, I unfortunately only have one video so I hope to come back and have more videos to share with that in mind. But I want to focus on some of the work that we've done and how it helps us think about the surgeries that we do, certainly before the OR and then during the procedures. I have one disclosure that's not relevant. What I wanted to start with though, for Dr. Cohen, since he was here, and it was before my time, but I don't know if it was quite as long as he says, are some of the things that we've been doing here at Yale. And so we really are the premier academic neurosurgical oncology program in Connecticut and we're honored to be that. We have the highest volume of brain tumor patients in surgeries and in the last several years, we have nearly quadrupled the volume of brain tumor surgeries that we have. The cases that we have are more complex, simply because we have other neurosurgeons in the region who are referring those cases to us. And every tumor that we remove or even biopsy undergoes whole exome sequencing, which really has been such a valuable tool to us. I lead the multidisciplinary tumor board as well as Precision Brain Tumor Board, where we use that whole exome sequencing data in real time. And I'll speak to that with regards to meningiomas today. Just some examples of cases that we see here. My fellow pulled these cases for me, just some recent ones from before, but some complex meningiomas or motor strip glioblastomas, epidermoids of the skull base, meningiomas of the sphenoid wing, which we'll talk a little bit about and the relevance of that, acoustic neuromas, more skull base meningiomas, more epidermoids, intraventricular, fourth ventricular tumors. And again, just more examples of pre and post cases that we do. And these are quite routine to us and what we do here every day. And so meningiomas has been a big focus of interest for me and for others here at Yale. Reason why is these are a little bit cleaner tumors from a genomic standpoint. They're certainly not as heterogeneous as the gliomas or glioblastomas. And what's also peculiar about them is that some benign grade one meningiomas can behave more aggressively like grade twos or as others can behave, maybe not as aggressive as you might think. So this has been something that I've been focusing on clinically, of course, tackling these more complex meningiomas but then also translating what we have learned in the lab and what we continue to learn in the lab. And so really we've asked the question is there really is such thing as a benign meningioma? How does the underlying tumor biology affect clinical behavior, recurrence and survival? And again, why do some lower grade tumors behave more aggressively? This is a patient who was referred to me. He was initially seen at an outside hospital in 2017 and he has this convex named meningioma. From a surgical standpoint, very straightforward for its removal. He was initially seen again in 2015, had a recurrence though in 2017 after undergoing a quote unquote near total resection. At that time he saw other neurosurgeons and providers, he hadn't seen me yet, and he was offered radiosurgery and underwent radiosurgery. And you can see in 2019 the tumor continued to grow and now associated with even more edema. And he was having issues himself with intractable seizures and weakness, so he was referred to me in 2019. I ended up performing a very straightforward gross total resection. His weakness improved, his seizures went away. The question that I was left with was, could this have been managed or handled better or differently in the first time? This is another patient who underwent a bifrontal crani for meningioma in 2014 by another neurosurgeon. You can see that the defect involving his frontal sinus and he was told it was benign, they got it all and he was quote unquote lost to follow up. He returned with these scans in 2016 with visual changes in pap edema and his outside hospital neurosurgeon referred him to me. With my colleagues in plastics reconstructive and ENT, we ended up taking him to surgery, performed a gross total resection. This is just some of his abdominal rectus flap that actually became a little smaller once the surgery, once the swelling went down after surgery. But could this have been managed for different, based on the biology of the tumor, the initial time? And then of course here is a foramen magnum meningioma. Dr. Cohen certainly knows that these can be quite challenging tumors. And this was incidentally found, but you can see not very much room at the foramen. So we ended up removing it. I unfortunately don't have a video, but I do have some intraop pictures which are beautiful, which show the involvement of the vertebral artery and that being carefully dissected out. And then of course, the lower cranial nerves being preserved. She did well, went home two days after surgery and was a grade one meningioma. But of course, you know the risks that can be associated with a surgery like this can certainly make this not so benign. And so the last decade or so has really afforded us a great understanding of the genomic landscape of meningiomas and even more so now with epigenomics and other aspects that are considered. But for this I'm gonna focus on the work that we have done and specifically with understanding the genomic landscape of meningiomas. We know now based on approximately 80% of sporadic meningiomas have driver mutations in these somatic genes, the ones that I have in this diagram here. So the vast majority, about 50% of meningiomas, and these are sporadic meningiomas, have a mutation in NF2. And this can be with or without chromosome 22 loss. As you can see over to the left, and I'll focus on this on the next slide, these tumors can have chromosomal instability and copy number variations and this can lead to more aggressive meningioma formation and that's been something that has been shown from here. In addition, these tumors can co-occur with a mutation in a sequence transcription factor gene called SMARCB1 And that can also lead to meningioma formation, and again with co-mutation of NF2. Of the non NF2 mutant tumors, the most common here is a gene that is called TRAF7, that prior to the discovery in 2013 in the science paper that was published here from the Genal Lab, it had not been found to be relevant in neoplasia. TRAF7 mutations typically co-occur with mutations either in the PI3 kinese signaling pathway, specifically KLF4, which is one of the four yamanaka factors, or can co-occur with a mutation, sorry, in the PI3 kinese signaling pathway, which is AKT1 or it can co-occur with with KLF4. I misspoke of that being in the PI3 kinase signaling pathway. Other mutations can be in the hedgehog signaling pathway. That can either be typically SMO or SUFU, as well as PLR2A, which was more recently discovered. And then another sweet stick transcription factor gene, which is SMARCE1, which can often be seen in spinal or clear cell meningiomas. When I was talking about aggressive pathway to meningiomas, so much like gliomas, meningiomas can be high grade either because they arose as a de novo high grade meningioma or they can progress from a low grade to a high grade. And so the Genel Lab here as well found that here in these circumstances there's usually a mutation in NF2. These tumors will have chromosomal instability and or co-mutation with a SMARCB1 mutation. And this can lead to a de novo atypical meningioma pathway. And so these tumors present as grade two atypical meningiomas. That's different from those that acquire a TERT promoter mutation and progress from low grade to high grade. And I'll show you a little bit later in the talk how that's relevant clinically. So this is a fairly simple study that we did that we published in Journal of Neurosurgery, profiling more than 3000 meningioma samples and correlated with clinical data. And so here we just looked at really the basics for correlating genomic subgroup. One of the aspects that we further refined was something that we had defined and it was really my role in the science paper back in 2013 was understanding meningioma subgroup with its correlation with location. And so here, you can look at an MRI and the location can really lend insight into the underlying genomic subgroup. And so here, NF2 mutant tumors typically occur posterior to the coronal suture. They also have a laterality preference. And so these tumors typically are the ones that are along the convexity. And when they do arise along the skull base, they tend to be more lateral than medial. They can occur anterior to the coronal suture, but usually when they do they have a co-mutation at SMARCB1 and they're usually midline along the faults in those circumstances. In terms of the skull base, I think of the sphenoid wing as really having mutations in TRAF7, either alone or with co-mutation of KLF4 or mutations in the PI3 kinase signaling pathway like AKT1. The hedgehog signaling pathway mutations typically are in sporadic meningiomas that are along the olfactory groove or even in the plenum sphenoid alley, so those are those midline tumors. POLR2A are usually the ones that are more located in the sellar or deep down along the sinus and even out into the CP angle. And of course, just to mention again, that we know for about 80, 85%, the genomic driver mutation in sporadic meningiomas, but there's a 15 20% that is mutation unknown. This is a summary of some of the relevant findings, which I think most people have a good understanding of, but I think it was a good confirmation and a good review and worth mentioning here as well. So NF2 mutant tumors, typically more common in males. They're amongst the largest at presentation along with those olfactory group, hedgehog mutant tumors. They typically present in older patients later than others. And we found that these patients were more likely to undergo preoperative radiation. NF2 and SMARCB1 mutations were more common in higher grade tumors, along with an elevated proliferative index. KLF4 mutant tumors, these were more common in females. They're associated with secretory histology, which has been shown to be associated with higher degrees of edema and they tend to present later. Interestingly, although they're quite rare, the POLR2A mutant tumors have the least amount of edema associated. They typically present the earliest, largely because they tend to be near the optic after apparatus and they, in our studies, were all grade one. So a few years later we decided to focus on specifically looking at different clinical correlations. And so one of these studies that we looked at was sphenoid wing meningiomas, and I thought this was a good study to review here 'cause this can be relevant when we're thinking in terms of surgical approaches. And so for these tumors, as we know, they sometimes can really involve the sphenoid bone into varying degrees and we don't know necessarily how aggressive or how relevant that bone involvement is. As we know, when there's proptosis of the eye and the orbit and there's bowing into the orbit as well, of course that needs to be decompressed and removed for a cosmetic and oftentimes pain or neurological function with use of the eye, but also from a pathology standpoint, how relevant is that? And that's something that we sought to look at and further identify the sphenal orbital meningiomas and what's the relevance of that hyperostosis? So in our study we looked at 64 patients who underwent surgery by me for sphenoid wing meningioma and their tissue underwent whole exome sequencing, all underwent the standard approach that I use, which again, is typically a pterional approach. And then what I do focus on is that extradural, dissection, removal of the sphenoid wing, drilling down the anterior glenoid sum as well to really get that exposed. And then typically in conjunction with some of my colleagues in oculoplastics as well as reconstructive surgery, the key is really to decompress that orbital wall and decompress the orbit as you can see we did for this patient here. And this was her, of course, pre-op here she is really immediately post-op and you can see already that there's such a difference in her right eye. Not to mention that the tumor was removed, as you can see on the post-op scan. So when we looked further, we classified bone involvement and we came up with this classification system based on really no bone involvement, which you can see here, which is type one. And you can see that meningioma on the MRI. But really no involvement of that sphenoid bone and then compared it to where there was hyperostosis, tumor invasion and a combination of the two. And what we ended up doing was using the contralateral sphenoid wing as control for comparison. And so you can see here, here's the intracranial meningioma, that soft tissue mass and you can see the bone growth associated with it. And on CT it really just looks like hyperostosis. Whereas here, type three is just frank tumor invasion and actually there's really no intracranial component of the meningioma. It's all really in this sphenoid bone. And then finally type four, which is invasion and hyperostosis. You can see a combination between the two. And then again, defining these pheno orbital meningiomas where they have that real marked hyperostosis and bone overgrowth and bowing into the orbit. So what we found when we looked at clinical and genomic characteristics, which were pretty much what we expected, again based on how I started the talk, most sphenoid wing meningiomas harbored a TRAF7 mutation followed by an NF2 mutation, and about three quarters of all sphenoid wing meningiomas had some degree of bone involvement, whether it was just hyperostosis, invasion or both. When we looked at bone involvement with patient and tumor characteristics, we found that tumors with invasion were more likely to be higher grade and they were more likely to be larger in size. The sphenoid orbital meningiomas were found to be in nine patients, a smaller subset, and most of them, the majority of them had hyperostosis rather than that frank tumor invasion. They were also just exclusively seen in women, which we noticed, and they typically presented with proptosis like the patient I presented. When we looked at some genomic subgroups and bone invasion, we found NF2 mutant sphenoid wing meningiomas, which are here on A, were more likely to have bone invasion, older age at surgery, and larger tumor volume. Whereas the TRAF7 mutant tumors, which is panel B, were more likely to be associated with hyperostosis and a smaller tumor volume. So when we look at A, we can see that the bright pink is the sphenoid bone and then where the asterisk is is the frank tumor invasion, compared to B with the TRAF7 mutant tumors. Those just seem to be a lot more hyperostosis or bone growth without brain tumor involved. Looking at the spheno orbital meningiomas, compared to the non TRAF7 mutated tumors, those that had TRAF7 mutations had a higher percentage of spheno orbital meningiomas. So this was marginally significant likely because of the small sample size. Having a sphenoid orbital meningioma was a strong predictor of TRAF7 alone mutation. So again, looking at that image can help predict what the underlying mutation is. And this became stronger after we adjusted, but again, probably limited because of small sample sizes. When we looked at tumors with invasion, we found that they were nearly 30 times more likely to have an underlying NF2 mutation after we adjusted for age at surgery and tumor volume. Whereas hyperostosis only were over four times more likely to have a TRAF7 mutation. So again, tumors with that frank invasion of the sphenoid bone typically are associated more commonly with NF2 mutations, whereas hyperostosis really just associated with TRAF7 mutations. And so we concluded this and actually our image was on the cover of the Journal of Neuro-Oncology. Tumor invasion correlates with NF2 mutation and higher grade meningioma. So this is important, so while we're thinking for surgery and for surgical planning, if you see the preoperative MRI and there's involvement of the frank tumor in the bone, it's super important to be sure that you get a complete safe resection of that tumor, not only for the cosmetic portion of that, but really for the completeness from a neurosurgical oncology perspective. Hyperostosis is more likely to be seen with TRAF7 mutant meningiomas, which we'll talk about the relevance of that a little bit later. The significance still remains a bit unclear and it's something that we're studying further now in the lab. But here, the aggressive surgery is probably more aimed at relieving the the orbital symptoms in the proptosis and getting a good decompression from that standpoint. Switching gears, looking at seizures and meningiomas. And so unlike gliomas, it's a little bit odd that meningiomas may cause seizures simply because they're extra axial and it's a little bit less intuitive, but about 30 to 40% of meningioma patients will suffer from seizures. We sought to see if there was any genomic correlate to this, so we reviewed our clinical and whole exome sequencing data on about 400 patients who were treated from meningioma. About 17% of these patients presented with preoperative seizures. In univariate analysis, we found that patients with preoperative seizures were more likely to have tumors that were higher grade going along with that atypical histology, elevated proliferative index, convexity location, edema, brain invasion. And for the first time we found that they were more commonly seen in patients with somatic NF2 mutations. When we looked at multivariate analysis, we found patients with preoperative seizures were more likely have tumors with edema, atypical histology. And here the NF2 mutation only approached significance. We looked into why and performed a mediation analysis, and here what you can see with this diagram is that NF2 mutation is not sufficient to drive seizure occurrence. That makes sense, it's a mutation in a gene, but rather its effect is indirect and it's mediated through a higher grade than edema. And so that is what we know to be associated anyhow, and certainly that seems to be associated with seizures as well. When we looked at postoperative seizures, seizure freedom was achieved in our cohort in about 83%, seems irrespective of extensive resection, postoperative seizure patients were more likely to have edema, recurrent tumors, and postoperative radiation. When we looked at progression-free survival, we found here patients with preoperative seizures, and these are here on the left, had significantly worse progression-free survival compared to those without preoperative seizures, while the progression-free survival did not differ between those with and without postoperative seizures. So it's really that preoperative seizure that should be a marker that you might be dealing with a more aggressive meningioma upfront. And so patients with meningiomas who present with seizures may indeed have a more aggressive meningioma and that might guide you to be, again, as safe as possible but surgically aggressive in those circumstances. We need further work and we're doing further work, but certainly correlating that NF2 mutation is relevant and something that can help predict and help guide as well. And then the final story I wanted to share before going back to some case illustrations is one that we published in Neuro-Oncology. This is with Mark Youngblood, he was an MD PhD student with us here at Yale, now a resident at Northwestern. But it was really the first study to identify molecular subgroup as an independent predictor of recurrence along with grade and prior recurrence. Here we had about 500 meningiomas and our length of surveillance was about 54 months. And so here, overall rate of recurrence at two years was 12% and this was really appropriate amongst low grade and high grade. We found that four subgroups had appreciable rates of uncensored recurrence at two years. And so here, hedgehog signaling and PI3 kinase signaling pathway mutations typically recurred sooner or had higher rates of recurrence as well as NF2 mutations in TRAF7. The remaining three groups, KLF4, POLR2A and SMARCB1, had only one recurrence amongst those groups. And so that, especially the SMARCB1, because I told you earlier that that can be associated with higher grade and elevated KI67, how does that fit in? And we found that that seemed to relate to extent of resection. And so those are those parafoll C, anterior parafoll C tumors that perhaps are getting a more extensive resection with typically we remove the faults during those procedures. In any event, these four groups had 22 times higher rate of recurrence compared to the other groups, and this was still held at 17 times higher when we only considered grade one samples. What we found here in this figure I thought was pretty interesting. And so at 60 months hedgehog, NF2 and TRAF7 mutant meningiomas all had elevated rates of recurrence that you can see. But what was interesting was that the PI3 kinase signaling pathway molecule mutations, those tumors recurred within in the first 24 months. So they had really early recurrence and this was even in WHO grade one tumors. POLR2A mutant meningiomas showed several recurrences, but these were at later time points. And these are a relatively rarer genomic subgroup and so we only at the time had three POLR2A mutant tumors in the study, so probably something we need to look at more with higher numbers. But in the end it seemed that the PI3 kinase mutant tumors recurred earlier, POLR2A later, and in the hedgehog, NF2 and TRAF7, steady rates of increased recurrence over time. On univariate analysis with progression-free survivals, not surprisingly significant associations with grade, convexity location, atypical histology, elevated proliferative index, prior recurrence, gross total resection, and female sex were protective. So positive significant associations. NF2 mutant meningiomas were negatively associated with progression to pre-survival, whereas KLF4 were positively associated. And in multi-variate analysis, grade and previous recurrence were identified as significant covariates. NF2 samples were not observed to be an independent factor, so very similar to the seizure study that we had, the NF2 mutation itself is not sufficient to drive, but it depends on other factors such as higher grade and other associated aggressive features which can be associated with NF2 mutation. So going back to our studies from the beginning, that first patient that we presented, this is a patient who had a convexity meningioma. The tumor seemed to to grow rather quickly after near total resection associated with seizures. Could this have been better predicted or managed the first time? And the answer is yes. And so this is an example of the integrated diagnosis that we receive from all of our patients who undergo resection here at Yale. So you can see here the clinical diagnosis. So histological diagnosis is atypical meningioma, WHO grade two, and that was what was confirmed histologically. And so you might say, well, maybe the tumor progressed from a low grade to high grade and that's what we were seeing. But in essence what we see here when we look at the whole exome sequencing data is that there is the NF2 mutation that we see here along with chromosome 22 loss, but there's also a relative fair amount of chromosome instability. So there's these other deletions and amplifications seen in other chromosomes, particularly chromosome 1P and some others that are known to be more aggressive on a lot of the grade C and B work that has been done in this topic. And so the way we would put this together was this was likely a de novo atypical meningioma when he first presented and usually here at Yale, we'll totally resect those tumors and then we usually will follow it up with radiation and probably in the absence of that, the patient had a higher risk of recurrence and that's what we're seeing. This is another patient, and the patient was actually one of my colleagues, in 2017 had this really large sphenoid wing meningioma. He performed a resection and just left a small amount of tumor that was stuck to the optic nerve. And the patient was a 70 year old patient who had presented with blindness or vision loss, I should say, and then also left a small amount of tumor in the cellar to preserve function. And so this is pre-op, this is post-op, which was in January, 2018. The pathology or histological diagnosis was WHO grade one. You can see about five months later or so, there's recurrence, and so this is not what you would expect, even though it wasn't totally resected, there was a small amount of tumor that was left behind. You still wouldn't think a WHO grade one tumor would have that kind of growth in such a short amount of time. At that point, the patient then underwent radiation and you can see follow up about two years later or so, there's further growth and this time on the right side. And I ended up assuming the patient's care and operated on her a few more times for continued growth. She was enrolled in clinical trials and such, but all the while the histology remained WHO grade one. And this is, again, an example of our integrated report and you can see here the AKT1 mutation. So again, as I mentioned, those tumors that have mutations in the PI3 kinase signaling pathway, we have found that they recur at higher rates and they do seem to recur earlier. And so this was certainly within that 24 months or so that we had found. Similar patient, another sphenoid wing meningioma. This is a 50 year old woman when I saw her. Prior to me seeing her, she had had a resection in 2006 for this right-sided sphenoid wing meningioma. I don't have the initial images. She then underwent stereotactic radiosurgery later in 2006 and fractionated radiation in 2008, another surgery elsewhere in 2010, repeat surgery in 2016, she enrolled on Priscilla's trial in MGH in 2009. And then she failed in 2020 and Priscilla was kind enough to send her to me. You can see very vascular tumor, of course with the relevant vasculature involved. We took her and performed a nice resection and she actually improved. She had presented also similarly in a wheelchair with weakness and she actually improved. And what was interesting is when we compared her pathology to this resection compared to others, it remained WHO grade one. But again, there's that AKT1 mutation that we see in the PI3 kinase signaling pathway. And then this is the CNVs, with again, chromosomal instability and some of the more aggressive types of CNVs such as chromosome 1P deletion. And then this was a patient who presented with multiple meningiomas. And this is something that I didn't touch upon in the talk, but would be happy to in the future, what to do about multiple meningiomas? Does one meningioma predict another? We ended up, I'll just go back, we ended up resecting the tumor on the left. This was an incidental finding, but associated with some edema. And you can see it has involvement with the carotid and then the MCA. And so this is my one video from the neurosurgical atlas. I hope to bring back more in the future. And we'll start to play it. And so this is the frontal lobe here. And again, this is left side temporal lobe here. And you can see this meningioma, of course, arising from the skull base. There's the carotid artery. This is gonna be the bifurcation of the ACA to the MCA over here and then dissecting it free from the brain. I always say one of the big secrets to my success in working in these areas is really getting the control of the vascular supply of the tumor. So going right down to the skull base and getting that vascular supply. And then that really turns what could be quite a bloody tumor into a pretty dry tumor. And I always use lumbar drains in these cases, especially if the optic carotid cistern is obliterated with tumor. So that way, as you can see, we don't use any brain retraction during these approaches. Again, taking the little last bit off of the skull base, and this was kind of what I described before, that pterional approach with taking down extra dually the sphenoid and then down to the kelois. And then here now we're just dissecting it free and really just removing it on block off of the frontal lobe. And you can see we're monitoring motorable potentials and other neuromonitoring. And there we go, removing it. And I guess trying to remove every last bit, so a little bit more along that skull base, which is important. And there's our anatomy. We can go to the next slide where we show the anatomy. And here it is from that case. And so here, of course, the optic nerve and the carotid and and such. And this is after the tumor has been removed in the third nerve, and there's our postoperative scan. So going back to our whole exome sequencing data and our integrated diagnosis histology was WHO grade one. And here we're seeing TRAF7 and AKT1 mutation. So the question is, what does that mean? Does it mean that the risk of it coming back and recurring in a short period of time is greater? It's possible. So it's something that we need to keep a close eye on. Also, what implications does it have for the other tumor? And I can tell you without going into all the science that we've done, that one genomic profile of a multiple meningioma really does not shed light on another. And certainly even the distance between one tumor and another tumor in the same person does not necessarily shed light. And so we typically will treat them independent of one another. And this patient is an older patient and we've just been watching that other tumor for now. So for all of our patients and all of our brain tumors here at Yale, we really rely on the Precision Brain Tumor Treatment Program, and again, integrating the diagnosis, not just relying on histology, but using the histology and then also using the whole exome sequencing data to really understand the potential behavior of the tumor and then what other treatments, such as radiation, might be beneficial or how close in follow up should we follow these patients and their tumors. So in summary, not all meningiomas are benign, even the benign ones. And I think that our work, as well as others who are looking at epigenomics and other aspects of the total story, are really helping to show that. The clinical trials that are out there are really important, more and needed. And I think more and more will be focused on the molecular makeup of these tumors. Just a quick thank you, of course, to our patients who contributed to these studies, to my clinical team who we see down here, our nurse practitioners and our nurses. We have a cast approved fellowship here at Yale in neurosurgical oncology as well. This is my last fellow, Neland, from last year. This is Saul, who helped with some of these slides. And then our research team, this is Joe, our database manager, of course maintaining these databases. Joanna is a fifth year student from downstate who's applying to neurosurgery, who is wonderful and has been working with us this year. Some other students, Shari and Sagar who was with us and Lawrence, who scrubs all my cases in the operating room. Not to mention everybody else in my lab, Moliterno lab and other colleagues in neuropathology, neuroradiology and genetics would say that.

- Jennifer, I really enjoyed the discussion. As you know, I have been always interested in your technical trajectory and see what are your pearls for young neurosurgeons who wanna reach technical excellence. Obviously you have done that beautifully. And I wanna see at your level, what is the top three advice, pieces of advice, you have to people at your level? Let's say if you had, if you're talking to yourself and when you just graduated from residency, what would be three pearls you would definitely let them know?

- I think the major pearl, so it might turn out to be three, but I think the major one is to be available, do a good job, and take on challenging cases and don't shy away from them. And I think, of course, with all of that comes trusting yourself, having good insight into yourself. Are you able to do these cases? Are you able to take these on? When I started out, I developed pretty quickly a very skewed practice. I really took whatever I could get to develop my practice and a lot of those cases were cases other people didn't wanna do. And I think I had excellent training, both here at Yale and then in fellowship, to really tackle them. And I've seen that as I've developed my expertise and I've become more experienced, I can push those limits. So I think knowing your boundaries and at what stage you're at, but certainly being available, willing and able to do things that are harder and more challenging is really useful and helpful. And then having insight into yourself, knowing your own limits is really useful.

- I like the triple A, you know? It always starts with availability, applicability and ability. You can see the ability, the last one in the list. So how do you develop that confidence? Obviously you had a self of confidence in yourself to take on more challenging cases, so how would you advise people to develop that confidence, Jennifer?

- So I think what I found, and what I did was, I was never in a situation where I would have other people more senior scrubbing. I just didn't have that type of setup or situation. So I think if you're in a situation like that, you rely on yourself to really trust yourself and to develop those skills and to gain that confidence in yourself. I think a huge thing for me has been just paying attention to details. The more you pay attention to details, the more complication avoidance that you have, I think the better, of course, your outcomes are, and then the better your outcomes are, the more referrals you get. And then the more referrals you get, the more surgeries you do. And I think it's like anything else, the more you do, the better you are. And that, I think, has been the case for me. And I think always staying humble and always realizing and recognizing that every case is a different case potentially, and no two cases are the same. And never let your guard down. Even if you think that this is something that is relatively straightforward, be prepared for things to go wrong. And certainly in those bigger cases, being prepared with lumbar drains or ventricular catheters or aneurysm clips in the room or whatever it is, just always be prepared for things to go bad. And I think the biggest compliment I have received is when you know the residents or fellows says, "Well that looked really easy." And I think that's a huge compliment. But I think the real secret and trick to that is just being prepared and paying attention to detail and then you gain the confidence in yourself.

- Yeah, well said. Steve Jobs has always, when he was alive, he emphasized from Apple that it is most difficult to make a complex task simple. And in fact, those who make a task more complicated have less knowledge of the task than those who make it simple.

- I agree with that.

- If you want it bad enough, if you are committed enough to make the task simple, you are gonna be the one who can bring the ship home under turbulent conditions as a captain. So the more people actually make neurosurgery more complicated, the more they make it look like, so when you say attention to detail, I absolutely agree. However, there is a form of attention to detail.

- Right, yes.

- And I know both of us know that, that people are so intensely engaged in a case, that make it look so complicated and make it more difficult for the trainees to learn and make it for themselves more difficult to accomplish that in fact, the case goes much worse than someone who really is much more confident like you, more relaxed, more at ease with managing unexpected situations and therefore make a very difficult case effortless.

- So I think that's a great point and thank you for clarifying that because I think paying attention to detail and being prepared is the preoperative focus, you know? And so looking over those cases ahead of time, thinking of all the things that can go wrong and being prepared in those circumstances, in those situations. But you're right, when you show up to the OR, you keep it as simple as possible and just focus on what you need to do and do what you need to do and then move on. And I think the patients do so much better with that and you do so much better with that as well.

- I agree with you, I agree with you. So yeah, I wholeheartedly believe that keeping it simple, focusing on important details but not over complicating things, just like you said, details are important, I'm not saying that they aren't, they are for sure, but in a format that really makes the whole operation and the flow simpler. So again, I want to thank you Jennifer, look forward to your next success. Keep up the great work, not only with your cases, your technical skills and a great role model that I said you are for the younger generation.

- Thank you so much.

- Thank you again for being our guest today.

- Thank you for having me.

- All right, have a good afternoon.

- You too.

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