Craniofacial Resections for Malignant Disease of the Skull Base

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- Colleagues and friends, thank you for joining us for another session of The Virtual Operating Room. Our guest today is Dr. Franco DeMonte from MD Anderson, really a Mecca for skull base surgery, and Franco is in fact the Director of Skull Base Surgery at MD Anderson, today he will talk to us about complex craniofacial approaches for surgical resection of malignant disease at the region. Franco, thank you so much for being with us. You are truly an accomplished and world-renowned neurosurgeon in this area and I'm very much looking forward to learning from you so please, go ahead.

- Thanks, Aaron. We're going to talk about craniofacial resections for malignant disease of the skull base as part of the discussion about skull base malignancy in general. The first slide tries to give a relative overview of what we see here at MD Anderson over the past 28 years, the majority of the malignancies we see are in the anterior middle skull base. The malignancy of the posterior skull base is really decidedly rare. That's different than where we see our benign tumors where the posterior fossa where we see meningiomas and a lot of acoustics, is different. This is a different visual representation of the same data where the benign tumors are predominantly seen in the posterior skull base where malignancy is quite rare. And the malignant disease is most commonly seen in the anterior skull base and middle skull base. About 600 malignancies in adults we've surgically managed. You can see the distribution is different between the adult patient and the pediatric patient, where in the pediatric, about two-third- Sorry, three-quarters of the tumors are of the sarcomatous variety, whereas in adults about 40% are sarcomatous, and the majority are epithelial in nature. In the adult skull base, the anterior skull base is the most common location for malignancy and those malignancies are typically the sinonasal cancers. The further back you go in the skull base, the greater the percentage, the relative percentage, of sarcoma. Much different in children where sarcoma is the predominant pathology and they're more commonly located in the middle and posterior skull base. These next couple of slides are pie charts to try to give you a relative appreciation of, sorry- An appreciation of the relative incidences of the different types of tumors in different locations. You look at the anterior skull base and then you take squamous cell carcinoma, olfactory neuroblastoma, adenoid cystic carcinoma, adenocarcinoma and sinonasal undifferentiated carcinoma, together, those are the sinonasal cancers and they represent the majority of the tumors seen here where the sarcomas are just under a quarter of all cases. Of the sarcomas, the chondrosarcoma, chordoma and osteosarcoma are the most common pathology seen in the anterior skull base. In the middle skull base, sarcomatous tumors predominate, although squamous cell carcinoma and adenoid cystic carcinoma are seen here mostly from posterolateral extensions from the sinuses or through perineural extension into the middle skull base. Of the middle skull base sarcomas, chondrosarcoma is the largest single pathology although rhabdomyosarcoma, hemangiopericytoma, osteosarcoma form relatively equal portions of the sarcoma pie. In the posterior skull base, the predominant tumors are chordoma and chondrosarcoma. If you've been keeping track, that's 35 different tumor pathologies with over 20 varieties of sarcoma and 15 non-sarcoma pathologies. It really highlights the need for these patients to be managed as part of a multidisciplinary team of physicians, surgeons, and radiation oncologists in order to maximize their outcomes. And this case, I think, represents a good example of that. This is a young man in his twenties, presented to us with rapidly worsening obtundation, and you can see he's had a hemorrhage into his right frontal lobe associated with this large sinonasal malignancy. So, because of his rapidly progressing obtundation I decided I wanted to get that hematoma out, take out that mass in his brain, but I didn't want to spend all the time doing a formal craniofacial resection. So, we went ahead and removed the intercranial portion of the disease and left the sinonasal portion intact. The pathology was sinonasal undifferentiated carcinoma. After his cranial operation, he went ahead and got four courses of chemotherapy with etoposide and cis-platinum. And as you can see in the bottom panel of slides, there was a definite reduction in the size of the tumor. And on the CAT scan at the far right, there was actually some return of the bone formation of his ethmoid sinuses and terminates. Went ahead and did a formal craniofacial resection and followed that with 60 gray radiation therapy and 30 fractions. And he has been without evidence of disease now for actually almost 12 years. But, the interesting part of this story is the pathology from the second resection where no tumor could be identified in that large sinonasal component of the tumor, so the chemotherapy had completely sterilized this patient's tumor. Here's another case where this is clearly an unresectable squamous cell carcinoma of the cavernous sinus with extension into the posterior fossa. Patient was treated with carboplatinum, paclitaxil and gemcitabine, and 60 gray radiation with complete resolution of his disease and long-term survival. Based on these experiences here at MD Anderson, we looked more carefully at sinonasal undifferentiated carcinoma which is a particularly malignant sinonasal carcinoma, and we constructed a study where patients were given induction chemotherapy and then followed by either concurrent chemoradiation or surgery with post-operative adjuvant radiation or chemoradiation. We had 137 assessable patients. 95 of those patients were given induction chemotherapy. There were two groups, those that had a complete response, indicated by CR, or partial response, indicated by PR, and those that had less than a partial response which were either a stable disease or progressive disease. These are examples of those situations. The top one is a complete response, the PR, partial response, SD, stable disease, and PD, progressive disease. So when we looked at the group as a whole, the five-year disease-specific survival and overall survival were pretty close, about 55-60%. But when we looked at survival, both overall and disease-specific, there was a statistically significant difference between those patients who responded to the induction chemotherapy and those that didn't. And when we looked into this a little bit more carefully, we saw that the patients who received chemoradiation following their induction survived better and longer than those that were operated on after their induction chemotherapy. So, when we broke it down, and on the top two slides are the responders, the bottom two, the non-responders, in those that responded to their induction chemotherapy, there was a significant survival benefit by following that induction chemotherapy by chemoradiation therapy. Whereas those patients that were operated upon had a distinctly worse outcome, both in overall survival and disease specific survival. That's different in those patients who did not respond to chemotherapy. In the non-responders, their outcomes were maximized by operating on them. So, I think this was an important finding for us and when we asked why this was, we saw that, in those patients who got the chemoradiation therapy following their induction, they had a better distant metastases free survival and a better loco-regional recurrence free survival. So, we felt that the downtime those patients had after having had an operation was detrimental to their outcome. And so that's changed the way we manage these tumors, and the conclusions of that study were that two-thirds of the patients responded. Those that responded had a better prognosis, and those that responded who were treated with chemoradiation therapy had the best outcomes. Those that didn't respond are in a poor outcome group overall, but they, within that group, survived better if we operated on them and followed that with chemoradiation therapy. A secondary conclusion from this study is that the role of surgery and the care of patients with sinonasal malignancy really continues to evolve. That there needs to be a continued re-evaluation of the timing extent and goals of surgery as novel adjuvant therapies are applied. And us, as neurosurgeons, we as neurosurgeons need to be actively involved in the creation of these novel multidisciplinary, multimodal plans, and patient selection is gonna be critical in optimizing surgical outcome. When we talk about craniofacial resection, it's the combined transfacial and transcranial resection of sinonasal malignancies and it represented a paradigm shift in the management outcome for patients with these malignancies. And these techniques have been in use for over six decades, since the landmark articles in the 50s and 60s by Smith and Ketcham. Modern and long-term outcome data are really lacking, however. And we know that a lot of work has been done, the reason for some of this data being lacking is things have really changed. Over time, there's been a lot of work in defining the histology-specific prognostic factors, tumor biology, we have refined surgical techniques, we've honed radio therapeutic targeting and developed chemotherapeutic and biologic agents which are active against diverse malignancies. We were involved in a lot of these things, we were looking at specific tumor biologies, different operative approaches and paradigms, and the use of adjuvant therapies as we've just finished describing. So, when we look at our data, we try to be critical and to make sure we are not maintaining the gains that we've maintained since the description of these procedures. And when I call our data the current standard, it's MRI data. Before 1990, there was really no adequate way to image tumors preoperatively and postoperatively. This era was the first time that the extent of resection could be critically analyzed, the techniques of craniofacial resection, microvascular reconstruction and open skull base approaches were mature by now, and 3D radiation planning was uniformly being used. So, when we look at our outcomes by tumor site, which was the first sort of stuff that we did in the early 90s, in the anterior skull base, we were able to achieve a 63%, 2 year survival. In the lateral skull base, the overall survival was 81% at 2 years, and 53% at 5 years with a median survival of 5 years. In the sphenoid sinus, the overall survival was 55% at 2 years, 40% at 5 years, and not quite as good for squamous cell carcinoma at that time. Then we started looking more carefully at the different histologies and we looked at our sarcomas, where the high grade sarcomas had a 66%, 5 year survival and the low grade sarcomas, 85%. When we looked at olfactory neuroblastoma, the overall survival was 89% at 5 year, and 81% at 10 year. And the disease specific survival was 92% at 5 years but did drop to 58% at 10 years. So, we noted that the recurrences in those groups of patients tended to occur at the 5-7 year mark after the initial treatment. Survival in mucosal melanoma continues to be dismal. Our publication in 2010 showed a disease-free survival of only 18% at 5 years. More recent publications in adenoid cystic carcinoma, a 46% 5 year, 21% 10 year progression-free survival. Advanced squamous cell carcinoma, 77%, 2 year in chemo responders. We just published an osteosarcoma paper showing a disease-specific survival of 144.5 months, and in that paper identified as microscopically negative margins as the most important prognostic factor in those patients. And we looked at our infratemporal fossa carcinomas, our disease specific survival is 55% and overall survival, 36 at 5 years. So clearly, we're not there yet, and if you look at almost all those things for the epithelial tumors, we're in the mid 50%, 5 year survival range. This is a graph showing all our patients with sinonasal malignancies, not the ones in the skull base but all of them, and that's about 4,000 patients now. You see the patients who have the olfactory neuroblastoma and adenoid cystic carcinoma have the best overall survival, and melanoma, the worst. Things have changed over the last 28 years with respect to what kind of malignancies we see. I'm not sure I understand why that is, completely. We've seen a marked uptick in neuroendocrine cancers such as olfactory neuroblastoma, sinonasal undifferentiated carcinomas, neuroendocrine carcinomas, and a decrease in adenocarcinomas, squamous cell carcinomas, and different sarcomas. To some extent, adenocarcinoma could be decreasing because we're no longer doing much in the way of woodworking and leather working in this country. But, why others are increasing is unclear to us. Things have also changed in how we manage these patients. We looked in the 1990s, the majority of patients who came to this surgery were operated on by both a transfacial, an open-transfacial, and a transcranial approach. In the 2000s, we moved away from incorporating facial incisions into initially transcranial only approaches, and then into transcranial endoscopically assisted approaches. And in the last decade, there's been a marked movement towards endoscopic only approaches for specific patient populations. We published this back in 2009 initially, and along with a group in Italy, showed that in the correctly selected patients there was no difference in oncologic outcome between those patients operated on with a cranial endoscopic approach or with an exclusively endoscopic approach. We've updated that now, in 2020, and we haven't seen any change. Those patients who are appropriately selected for endoscopically assisted versus endoscopic only approaches have similar oncologic outcomes, and this is really an important piece of data because it flies against the conventional wisdom of having to do an en bloc resection. Now, these are not en bloc resections, they are done systematically but they are not done en bloc And yet, the survival is relatively equivalent. There is definite difference between the groups. If you look at our data from '09 and our data from 2018, both the endoscopic approach alone and the cranio endoscopic approach, we're seeing different tumors, the cranio, as you can imagine, the patients who undergo cranio endoscopic approaches have larger tumors, more extensive tumors, higher T-grade tumors. So, the discussion is no longer endoscopic versus open, the discussion is the criteria for endoscopic and/or open approaches. For example, both of these are great patients for endoscopic alone cases, not so much are these patients where there's a significant orbital invasion in the left panel, significant and wide intracranial and intracerebral invasion in the middle panel and very, very anterior disease in the last panel. That's a blind spot for the endoscopic approaches. Endoscopic approaches do have an excellent role in palliation, this is really data from the group out of London, England, who have been managing these patients with endoscopic surgery to reestablish airways while they're getting the appropriate chemo or biologic therapies. In our data over the last 28 years or so, the 2000s saw an increase in surgery in patients with more extensive local disease. I think we pushed the envelopes of skull base techniques and surgeries in order to deal with tumors that now are extending through the dura into the brain and into the infratemporal fossa. The last decade has seen an increase in patients with distant disease. Again, these may have been patients that we, in the past, had considered to be non-operable or did not recommend surgery because of distance disease, but because of our increased ability to treat these patients with chemotherapeutic and biologic agents, we're operating more and more on patients whose malignancy is not solely limited to the sinonasal regions. Also, in the last decade we've been using this scale, the Clavien-Dindo Scale of Complications. It's a nice way to classify the severity of complications, much better than minor major. For example, a grade 3A a complication would be the insertion of a spinal drain for a CSF leak or the elective evacuation of a hematoma or a wound revision. A grade 4 complication would be the emergent evacuation of a hematoma. In using this system in our patients, we looked at the , and from the 1990s to the 2010s we were happy to see a significant decrease in our incidents of grade 3B or greater complications. Specifically, there was only one death in our entire population of patients with sinonasal carcinomas. The other thing this analysis showed us is that when we used a lumbar drain, the complication rates were significantly elevated. And when we looked at all complications, and most importantly when we looked at patients with the intracranial hypotension syndrome, and what I mean by the intercranial hypotension syndrome, it's symptoms are postural headache which can be severe to incapacitating. On CT, it typically reveals a mix of epidural air and fluid, a combination of blood and spinal fluid accompanied by a concave appearance of the dura as though it was being sucked in. This is a very typical appearance of a patient with intracranial hypotension. Occasionally, it's manifested by tension pneumocephalus with a large epidural blood fluid collection, and in those cases surgical intervention is necessary. Most patients, however, were successfully managed with fluid hydration and placement of a high volume lumbar spinal epidural blood patch. And this complication was uniquely associated with lumbar spinal drainage. So, because of this we stopped using spinal drainage for a long time, and our CSF leak rate was about 3% for our open and cranio-endoscopic cases. When we started using the endoscope alone, the CSF leak rate increased from 3% to 13% and we reacted to that by reincorporating the use of lumbar spinal drainage into the management paradigms for these specific cases, for the endoscopic only cases. And interestingly, we have not seen the similar number of patients with the intercranial hypotension syndrome. I'm not sure why that is, maybe it's because we're not significantly elevating the dura away from the cranium over a large area of the frontal fossa, but to date we've not had any problems in that regard with the use of spinal drains in the endoscopic alone cases. So, as I mentioned, we have developed over the last 30 years from the classic cranio-facial resection with the facial incisions and the bifrontal craniotomy towards either a cranio-endoscopic or an endoscopic alone. The cranio-endoscopic approach is an excellent approach for a tumor like this, where majority of the tumor is intra-nasal but with midline extension. If you look here, there is extension over the overall rim so we wanted to add the craniotomy to make sure we got that margin. This is the operation we did from the cranial point of view, the bifrontal craniotomy, the ethmoid block resection, the repair with the pericranial graft. And this is a on the left panel, is the dural graft here. And the pericranium here being brought down into the anterior skull base. When we look at that from below, endoscopically, we have the orbits on both sides and there is that robust pericranium reconstructing the anterior skull base. So, the cranio-endoscopic approach is really the best of both approaches, it avoids facial incisions, it leverages the superior optical navigation of the sinonasal cavity afforded by the endoscope, it gives an panoramic unobstructed view of the entire floor of the anterior skull base. There's the ability to manage dural defects by direct watertight closure. It's a robust, reliable reconstruction with vascularized pericranial tissue. And there are improved options for orbital, cerebral and frontal sinus extensions of tumor. And it gives you an ability to directly visualize the adequacy of your reconstruction at the end of the procedure. So, these operations are done in the consense of the philosophy of how to manage malignant tumors. So, the questions that we ask ourselves is can the tumor be completely encompassed by surgical resection which carries acceptable morbidity? And, does the tumor pathology or biology make resection, with its attendant morbidity, worthwhile? And, is a complete resection necessary in all cases? Is there adjuvant therapy available? And is the patient a candidate, both medically and psychically, for this type of procedure? Especially those patients who will have to have significant facial surgery performed. Again, the multidisciplinary team is critical and every single patient is discussed in this forum in order to optimize their management and outcomes. We still fail, obviously, and the most common reasons for the suboptimal outcomes is that, despite our best imaging, our best intentions, we are unable to achieve microscopically negative margins. We are unable, at this time, to fully understand the biologic varieties of different phenotypes of different pathologic entities, you know, one squamous cell carcinoma is not the same as another squamous cell carcinoma. Or, we just choose poorly and don't identify the best patients for the best procedures. These have been traditional relative contraindications to extensive skull base surgery for malignancy. We have tried to look at these systematically over time and I'll present that in the next couple of slides. One of the contraindications in the past has been the invasion of the brain or the transdural spread of malignancy. We looked at these patients where we treated and we found a mean overall survival of 72 months, which is similar to the cooperative study data for patients who did not have intercranial extension, so we were happy to see that. What we found as the greatest discriminator of outcome was the ability to achieve microscopically negative margins. And so, I think if you are gonna operate on somebody who has transdural or intracerebral extension, every effort has to be made to achieve a microscopically negative procedure in order to make that procedure worthwhile. What we did not find, and this is supportive of the endoscopic approaches, is that we did not find that an en bloc resection made a difference. So, whether or not the patients were resected in an en bloc manner or whether they were resected in a piecemeal manner, there was no difference in survival. Next, we looked at patients who had perineural extension. Here, we have a classic MRI showing extension of a less maxillary sinus cancer into the anterolateral cavernous sinus, through the maxillary nerve at the frame and rotundum. We devised this procedure back in the early 2000s, where rather than doing a craniotomy following the transfacial resection of the tumor, we simply removed the skull base from below, enlarged the foramen rotundum, communicated it with the foramen ovale, communicated it with the superior orbital fissure, and this allowed us to access the medial middle temporal fossa from in front and allowed us to peel back the lateral wall of the cavernous sinus to expose those nerves back intracranially. And we were able, with that, to achieve resections of the maxillary nerve right back to the gasserian ganglion, as evidenced by the presence of ganglion cells in the bottom right biopsy. Now, in that paper, it was really primarily a technique paper, but of the seven patients that we'd reported, six were without evidence of local disease, and the one patient who died of progressive disease, progressed posteriorly in the infratemporal fossa but not at the intracranial or cavernous sinus sites. And in our series of patients, the adenoid cystic carcinoma, a microscopically negative resection imparted a significant survival advantage of 20 years compared to 10 years. So, we do pursue negative margins in these patients, as much as we can, safely. Tumor extension to the infratemporal fossa has always been identified as a negative prognostic factor for outcome. This is an example of an infratemporal fossa chondrosarcoma, which we resected through an infratemporal fossa subtemporal approach. When using this type of approach the things that you have to manage are the facial nerve laterally, you have to manage the mandible, either by transposition or removal of the upper ramus. And you have to manage the vasculature, you know, if you have to expose the carotid intercranially, then exposure of the carotid in the neck is done at this time as well. Here's the post-up scans showing skeletonization of the facial nerve in the temporal bone, V3 divided at the base of skull and the contents of the infratemporal fossa resected. So, when we wrote this paper in 2010, we had included 52 patients with anterolateral skull base malignancy, 39 of those 52 had infratemporal fossa extension. Our 5 year overall survival was about 53%, which is the number we we seem to be stuck at with many of these tumors. When we looked at, more recently, at 40 carcinomas in the infratemporal fossa, the disease specific survival was 32 months, 55%, 5 year, and the local progression-free survival was 69%. The only thing we really found that made a difference here was the presence of microscopically negative margins and age greater than 80. Because Karnofsky performance score less than 80 is a negative predictor, and positive margins were negative predictors of outcome. So, you got to have healthy patients and you have to get all the tumor out in order to maximize outcome in patients with infratemporal fossa carcinomas. When you're in the anterolateral skull base, you have to talk about the internal carotid artery in the cavernous sinus. Of those 52 patients in that paper, we had 8 patients where we did a cavernous sinus exclusion operation, either leaving the artery there and removing everything around it, or resecting the artery. And when we looked at that, we dissected the carotid and removed everything around it in four patients, and we took everything out, including the carotid artery in four patients. And when you look at this slide on your own, local recurrence in only one of four in those where you were more aggressive, but in three of four in those where you weren't. So at first blush, it's like, oh, maybe it is good to do a cavernous sinus exclusion operation. But when we analyzed the data, those patients undergoing internal carotid artery resection had a lower rate of local recurrence but they all died of regional distant metastatic disease, and one patient had a stroke. And the overall median survival for patients not requiring cavernous sinus dissection, or ICA resection, was twice that of patients undergoing those maneuvers. So currently, we cannot advocate surgery for high-grade malignancy when it encases the cavernous carotid artery. A lot of times, as I showed in some of the earlier MRIs, the tumor can extend into the orbit and we are asked, as part of a multidisciplinary team, to be involved with orbital exoneration. Here's a patient who had a recurrent deep orbital sarcoma going right up to the optic canal and the anterior part of the superior orbital fissure. Here, we're prepping her. We have circumferentially incised the orbital tissues here, and we're starting our bone cuts here in the keyhole region. Here's the zygomatic arch, sorry, sorry, body of zygoma. And as we continue, we create this bony division to separate the bony orbit from the cranium with the contents of the orbit. This is an artist representation of that, where we open the superior orbital fissure from lateral by taking out the greater sphenoid. And we can dissect the medial temporal dura back to give us access to the anterolateral cavernous sinus so we can make our division at the orbital apex as far posteriorly as possible, much more posteriorly than any approach to this area from interior, as is more traditionally done. This is just showing the elevation of the medial temporal dura to give us more exposure of the superior orbital fissure. Here's the resection, the frontal dura's here, the temporal dura is here. Here is the divided superior orbital fissure and the divided maxillary nerve, intracranially. And then the optic nerve is going to be right here. And this is a free flap reconstruction, again, long-term survivor with microscopically negative resection. When we look at our patients with orbitectomy, we had 180 in this group that we looked at. Majority were male. Karnofsky performance score was generally good. Patients were troubled with pain, severe in 13 and moderate in 19. The majority were tumors that secondarily involved the orbit, and they came from the cranial base. Involved the orbital apex in nine. And these are the different pathologies of the primary tumors of the orbit. And these are all the secondary ones, I won't go into all that. But here's the outcomes, if you look at the histology versus the 5 and 10 year outcomes, those patients with various sarcomas actually were in the best outcome group. These tended a lot to be more low grade sarcomas, but the adenoid cystics came in second. They survive long, they tend to have disease which can be indolent over time. And then, as before, the worst outcome group in these patients were the melanoma patients. As I mentioned, we have loosened our indications for patients with metastatic disease to the skull base. This is a patient with metastatic leiomyosarcoma, clearly had disease in the lung, but this large ethmoid sphenoid metastasis was resulting in bilateral visual loss, so we operated on this patient with a, at that time we used a transbasal approach, although this may have been able to be done endoscopically now, but at that time we did a transbasal and it allowed us access to the anterior skull base. Here is the intraoperative view, you have the orbit here and here, optic nerve here and here, and this is the disease in the sphenoid sinus coming out now. Post-op scan showed a complete resection, we were microscopically negative. She never had recurrence at the site but died 29 months post-op of disseminated disease. So if we looked at our, at that time, we looked at our 27 patients, the majority had epithelial tumors and seven had sarcomas. We operated only to palliate symptoms in these patients. So, the reason for the operation, eight were for progressive optic neuropathy, we improved five of the eight, stabilized three of the eight, we gave one person partial oculomotor, and the other indications are listed here. So, in this small study, we didn't have any surgical mortality. We gave one patient a new 6th, and one with a transient 3rd. The median survival was 11 months, which is very much like the outcomes for surgical resection of brain metastasis. And like patients with brain metastasis, the majority of patients will die of progressive systemic disease. A few notes to go over is that survival was better than two years in five of seven patients with sarcoma, and over nine years in a patient with metastatic follicular thyroid cancer. So, there are these patients who can have long, good quality survival with resection of the metastatic disease. We wondered whether or not operating on old people, elderly, was it a a bad thing or good thing? And, you know, we knew that the elderly population was growing rapidly and that advanced age could be considered a relative contraindication. But we also knew that the elderly population currently, is healthier than in the past and can fully expect a life of 17 years once the age of 65 years is reached. So, when we looked at this group of patients, we had two groups, we had a group that was young, which was, I think, the mean age was 56, and a group that was elderly where the mean age was 70 or 72. And we could not find any difference in the oncologic outcome between these two groups. What we did see, however, is a significant difference in complication rate. When you look at the elderly who are outlined here in red, their incidents of systemic complications was three times that in the young population, and that could easily be explained by their co-morbidities. So again, in the red, the elderly group was significantly more likely to have hypertension, other cardiovascular disease and smoking history. So, we concluded that study by saying that age in and of itself should not be a contraindication to these kinds of procedures but that you have to aggressively manage the patient's co-morbidities in order to achieve outcomes that are similar to those achieved in a younger patient group. Early on, we wanted to know whether or not we were negatively affecting patient's quality of life with these kind of procedures, and what we did with these patients, we gave them a bunch of self-reported quality of life examinations and we paired those with neuropsychological assessments to make sure we're getting good answers on these self reported questionnaires. And what we found was that cranial fissure resection and the therapies associated with it, specifically, radiation therapy, rarely affected independence. The Karnofsky performance score was over 90 in 94% of patients, and the functional independence measure was over 117 which is independent, in 87%. When we looked at sub scores and sub scales, 100% of patients reported a good quality of life from a neurologic standpoint, and 94% of patients reported a good quality of life from a head and neck standpoint. But when we looked at the more non-specific, so the general questionnaire scores, 30% of patients reported a poor quality of life. And this is not uncommon, if you look at any surgical procedure where the investigators use a general scale, about 30% will report poor quality of life, and it's felt to be related to psychosocial changes and adjustments that accompany an illness and its treatment. So, this is the list I showed earlier about relative contraindications. I think we were able to show, through those series of investigations that we had, that these two remain today, relative contraindications. We've not solved high-grade malignancy of the cavernous sinus and carotid artery involvement, and we've not solved melanoma histology. There are some things in the melanoma world that are looking really hopeful, but as yet, they have not translated into improved survival in patients with melanoma in sinonasal cavities. Thanks very much, this is my presentation. I'm happy to be able to give this to you in this form. Thanks very much.

- I really appreciate the great presentation. It was very, very helpful. I think the management of these diseases have advanced so much. Reflected in what you have really presented in the lecture today, Franco, can you tell me what else do you think is in the future for treatment of these disease? What do you think is done to pike on this?

- Well, I think understanding the neoplasms is what's going to change. We're going to know what squamous cell carcinoma is going to respond to what therapy, and which one is not. So, molecular markers, epigenetic markers, those things are going to give us the clues we need to know how best to manage patients. And thankfully, our drug development people in the world know this too, and so these drugs are now being created. Where, in the past, we were identifying some of these things but the drugs weren't there. But now, they're increasingly becoming available. And I think as we get better doing that, the role of surgery is going to change. You know, right now we've felt the weight on our shoulders for these patients for many years, because without surgery, they're all going to die. But, I think that weight is being lifted and shared because we're seeing some really amazing outcomes with some of these new biologic agents and combined therapies for a lot of these malignancies. So, I think that is going to change the nature of what we do. Currently, for example, for sinonasal undifferentiated carcinoma, the surgical role here is only for non-responders, it's really not a front therapy anymore. So, that's really changed in just the last five years.

- I agree with you that the role of surgery will shrink as other more definitive therapies will take over. What do you think is the future in surgical treatment for those diseases, tumors, that remain? Again and then about what are your thoughts?

- Yeah, I think- In my opinion, the biggest stumbling block or the biggest barrier we have is when the tumors involve the vasculature. I think you can live without some cranial nerves, you can survive. If you stroke out a hemisphere, you're not going to, that's bad. Knowing how to manage that, however, is really difficult. We used to do a lot of vascular resections for malignancies of the skull base relatively, and we did not see an improvement in outcome, in fact, we saw some patients do worse overall. So, I think surgical techniques are there, I think the incorporation of endoscopic surgery has made a huge difference in reducing morbidity associated with a lot of the anterior cranial facial work. And I think we've seen that you can't skimp with that operation, the endoscopic operation, you can't skimp on the reconstruction. So, more and more now we're harvesting the pericranium like as part of that operation. Because, as you know, most sinonasal cancers, you can't save the septum, there's no local tissue. Using what's available that's not good or using an allograft is not enough. So, I think to really prevent complications from the, specifically, spinal fluid leakage from the endoscopic resection of sinonasal malignancies, the use of vascularized tissue is absolutely critical. So, I think that's made a big difference in incorporating endoscopic techniques into this surgery.

- Very good. I want to thank you again, Franco.

- My pleasure.

- Incredible lecture, really enjoyed it, and a lot of great pearls there, and look forward to having you with us in the future.

- Thank you, and thanks very much for everything.

- You're welcome.

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