Thank you to the organizers of this virtual session for the invitation and to Dr. McConn and Dr. Grant for inviting me as one of the esteemed participants. I'll be speaking on the topic of building an interoperative mapping program from my perspective here at the Barrow Neurological Institute in Phoenix, Arizona. Stimulation mapping oftentimes begins with neurosurgical oncology decision-making as the precursor, and decision-making for a glioma surgeon increasingly involves early intervention. For low-grade gliomas, the support for this has been substantiated by a variety of retrospective studies, but also prospective studies such as this one comparing two hospitals with different approaches to low-grade gliomas, with one favoring initial biopsy followed by observation, or correction, one's favoring initial biopsy and the other one favoring initial resection. And the data from these experiences and others is quite clear, which is that early intervention is favored and associated with an improved overall survival for low-grade gliomas. And other studies subsequently, including this one, have validated this concept. And more recently, data from colleagues at San Francisco has also confirmed this concept. With respect to low-grade gliomas, we know that greater extent of resection is associated with greater overall survival, and this relationship exists even at the intermediate levels of extension at 80% volumetrically and beyond. And in fact, there have been a variety of retrospective studies confirming incremental improvement in overall survival with incremental improvement of extended resection, with complete resection associated with very favorable overall survival rates over a five-year period. Aggressive surgical resection is also associated with a better malignant transformation rate for low-grade gliomas, and in fact, also associated with better quality of life, which many times for low-grade gliomas is manifested as a function of seizure freedom. And we have studies such as this from Joan Palu that have made this point and identified these incremental extent of resections, including this study from our group at the Barrow, identifying 80% as a threshold for volumetric extended resection to achieve INGLE1 status. Beyond these incremental, subtotal, near-total, and complete resections, we have the concept of the supertotal resection and experience from a select series of patients, such as those from Dr. Dafoe, that indicate to us not only the feasibility of this approach in the proper setting, but also the significantly increased survival benefit. For certain subsets of gliomas, such as insular gliomas, specialized approaches are required from a surgical perspective, but the consequences of these approaches in terms of progression-free survival, overall survival, and malignant progression-free survival mimic those in other regions of the brain, and as do the overall rates of these metrics. The role of genetics in low-grade glioma extended resection is still being evaluated, but clearly not every subtype of glioma behaves the same in response to cytoreduction. And here we have evidence of 1p92 co-deleted gliomas and their relatively mute response to aggressive resection over a 10-year period. This does not obviate the need for aggressive resection, but does raise the possibility that surgeons need to consider the risk-benefit ratios differently as a consequence of the genetic background of the tumor. Larger studies of amalgamated patients' data sets also conclude similarly. And in fact, we've seen this data as extrapolated from the TCGA data set. In the end, however, when the surgical decision is made, the opportunity for extent of resection has to be balanced against the risk of surgical morbidity. So, for low-grade gliomas, extended resection is preferred to watchful waiting. Complete and near-complete resections confer an overall survival benefit as well as improve rates of transformation, and now extended resection is being visited in the context of genetics. Higher gliomas face a similar reality. In fact, for higher gliomas, there are more rigorous prospective studies comparing biopsy versus resection. And despite the small sample size, these have reached statistical significance in terms of their conclusion that a craniotomy is preferable to a biopsy for any higher glioma patient in terms of overall survival. The fluorescence-guided surgery prospective randomized clinical trial undertaken by Walter Stumer and colleagues in the German network of centers that participated in his 5-ALA trial also emphasizes a similar conclusion. This was a large cohort of rigorously followed glioblastoma patients, and these patients were randomized to 5-ALA versus placebo, and this study was pivotal in demonstrating the ability of fluorescence-guided surgery to significantly increase the extent of resection on these patients. And as a consequence of this increase, there was an observed improvement and a doubling of six-month progression-free survival and a five-month survival benefit associated with greater extent of resection. So, while this study was not designed to be an extended resection trial, it still provides some of the most rigorous data in support of the value of extended resection, and it complements the many other retrospective studies that clearly demonstrate a favored relationship between gross total resection and mortality rates in glioblastoma patients. At a more nuanced level, the UCSF group and others have examined the value of intermediate extensive resection, not at the highest levels of 100% or near there, but rather at the intermediate zone between 70% and 90%. And using a very large and homogenous data set of newly diagnosed glioblastoma patients with 500 samples in the set, this study identified the incremental benefits of extended resection in glioblastoma, as well as a threshold of 78% to achieve a survival benefit in that cohort. Anaplastic astrocytoma and anaplastic oligodendroglioma, i.e., grade three glioma studies, have also been performed using T2 or FLAIR signal as a metric for extended resection, and in these studies identified approximately a 50% T2 or FLAIR extended resection threshold to achieve a statistically significant survival benefit. Once again, we have to regard extended resection in the context of the genetic background of what we are resecting, and for higher gliomas, a key differentiator is IDH1 mutational status. This narrative has raised the question of whether supertotal resection of higher gliomas, where you are resecting beyond the enhancement into the FLAIR, is of value for IDH mutant tumors versus non, and in fact, that story remains incomplete. Nevertheless, others have looked at this paradigm in the context of radiographic features of the tumor with a, quote-unquote, proliferation-dominant phenotype representing glioblastomas, where the majority of the enhancement is occupying the FLAIR, and diffusion-dominant, where the opposite is true. And interestingly, the survival benefit associated with FLAIR resection was more evident in the proliferation-dominant phenotype, likely representing the fact that that FLAIR signal contains a higher proportion of tumor infiltration as the other phenotype does. So greater extended resection in NUSS-diagnosis improves overall survival. There is an 80% extended resection threshold that seems to hold up across multiple studies for newly diagnosed glioblastoma, and in fact, has been validated similarly in recurrent glioblastoma. But all of this has to be tempered by the risk of neurological morbidity, which leads us to some of the extended resection techniques required to achieve these results, and these include employing natural subarachnoid planes whenever possible, designing approaches around planned points of entry, positioning patients to enhance gravity retraction, and using stimulation mapping to traverse functionally silent corridors. Intraoperative technologies, including fluorescence-guided surgery, intraoperative MRI, intraoperative ultrasound, intraoperative CT, have all been demonstrated as interesting and useful as well. At the fundamentals of brain surgery lies the delicate dissection of arachnoidal planes, and for certain gliomas, including those within the insula, such as this one, a transsylvian approach using the natural arachnoid planes of a patient with appropriate positioning of the patient so that the frontal and temporal lobes can spread apart naturally without requiring any fixed retraction is a very feasible, proven, and safe approach for the right tumor. These resections can be complemented using the operating microscope, lighted bipolars, and other instrumentation, but at the end of the day, they come down to the fundamentals of surgical technique, which is the cornerstone for any glioma surgeon. Arachnoidal dissections and transsylvian approaches for insular gliomas are generally favored for tumors that are accessible through the fissure directly. Those in the zones of the insula that are typically zone 2 are associated with a higher incidence of postoperative ischemia. Entry point selection for gliomas is a critical thought process that has to be undertaken in advance of any procedure. Here we have a grade 1 juvenile polycytic astrocytoma in the pulvonar of an 18-year-old patient where we take a lateral supracerebellar approach, cutting the tentorium, going above the trochlear nerve, and entering the pulvonar posteriorly using lighted instruments and navigation to visualize our target entry point. With a strategy like this, the first PL margin transgressed is the only one required, and it is the one associated with the pulvonar, which is an imminently resectable target. Naturally, for a grade 1, this can lead to a surgical cure in certain cases, and therefore an aggressive approach is justified. For thalamic gliomas and others that are near midline, interhemispheric trajectories and careful positioning of the patient can lead to ideal operative exposures. Here we have the utilization of gravity retraction with one hemisphere down, no use of fixed retraction or devices like that, and a very facile operative corridor using lighted instruments, again, to enter the lateral ventricle, identify the bulge within its wall, and then resect the tumor as we approach the third. This type of strategy for the carefully selected patient can be ideal, can be associated with minimal new neurological morbidity, and lead to effective cytoreduction. Stimulation mapping, of course, is one of the cornerstones of aggressive and safe glioma surgery, and it has to be tailored to the case. For some tumors, there are relatively well-defined planes between it and the rest of the tissue, and this enables an en bloc approach to the tumor, and for others, a series of non-functional windows have to be created through the cortex to identify the right routes to the subcortical tumor. Both strategies are valid, both strategies can require cortical and subcortical mapping, and both strategies can achieve excellent clinical and radiographic results. Fluorescence-guided surgery is now part of the standard of care for glioblastoma surgery, and we and others have expanded it for utilization within lower gliomas using intraoperative handheld confocal microscopes and other enhanced visualization devices. The premise for both approaches, nevertheless, is to maximize cytoreduction and to push the limits of resection within the confines of functional boundaries, so that there is a minimal tumor infiltration at the residual margins. The narrative for intraoperative MRI is well-known and well-documented. This is a strategy that not only can complement extended resection, but can compensate for intraoperative brain shift. Several groups have rigorously studied this technology using prospective study designs and have identified a clear association with intraoperative MRI utilization and improved residual disease profiles. This, of course, has translated to a survival benefit and again validates the concept of greater extended resection improving the survival of our patients. Intraoperative ultrasound technology continues to advance and has become an increasingly prevalent technology within the operating rooms of tertiary and quaternary care medical centers. Here we see an insular glioma with an intraoperative MRI visualization melded onto intraoperative navigation from the MRI. This intraoperative ultrasound visualization shows you the lenticular striates as you proceed closer and closer to them during the resection of the insular glioma. Intraoperative CT also has a role. It can be useful for tumors that are visualized on CT scan, including those with intratumoral calcifications and those that avidly enhance with CT contrast. This is a low-cost but very time-efficient technology that can be useful in select circumstances. So for higher gliomas, there is always this balance that has to be achieved between overall survival and the risk of surgical morbidity. For lower gliomas, the same is true, and this added benefit translates to better transformation rates. The higher glioma extent of resection threshold justifying a surgical intervention should be 80% or more, and we've discussed a variety of strategies that can improve tumor visualization. Ultimately, all of these strategies can be brought to bear in case examples such as this 74-year-old with hemiparesis, ward-finding difficulties in an abdominal hemisphere, enhancing lesion consistent with a glioblastoma. Management options for a case like this can be varied, and certainly can vary across institutions. The insular higher glioma is a particularly challenging location that can be approached through both transsylvian and transcortical strategies. Some groups in the past have tried to compare these types of surgical approaches for medial basal tumors and noted the significant risk of vascular morbidity associated with the transsylvian approach. This risk of vascular morbidity can be better contextualized in the setting of surgical zoning of the insula, as shown here, with four zones created by perpendicular planes through the foramen of Monroe and the sylvian fissure. These zones each have their own degrees of surgical freedom and insular exposure, and importantly, zone two, which is the posterior superior zone, is most associated with vascular injury due to the retraction required through a transsylvian approach. Nevertheless, tumors in these locations can be approached through both strategies, and here we summarize some of our experience with 100 consecutive cases that were variably approached through transsylvian and transcortical strategies, each using intraoperative stimulation mapping. These tumors were similar in terms of histology and varied in terms of their anatomical zones, in part because of the transcortical approach being favored for zone three tumors. Extent of resection was similarly achieved in both groups, and there were similar morbidity profiles. However, zone two, as expected, did demonstrate a higher degree of postoperative radiographic ischemia, and this risk seemed to be mitigated through a transcortical approach. Ultimately, this case that I presented to you as a case demonstration was approached through a transsylvian approach. The sylvian fissure split is a relatively easy strategy that does not require fixed retraction and can be performed under an operating microscope. This leads you directly to the insula and an intratumoral resection, taking care to preserve the peel margins around it, including the vasculature within the sylvian fissure. Separating the insula from these peel margins provides better anatomical definition, and using ultrasonic aspiration, one can safely resect these regions of the tumor until one is approaching the medial margins of the insula, where a stimulation mapping can help us identify and avoid the internal capsule. Naturally, avoiding the lenticular striates, which the majority of the times are pushed medially by the insuloglioma, is a key element of avoiding surgical morbidity. Nevertheless, for larger tumors in particular, a transsylvian approach is a very readily accessible strategy. Because of the size of these tumors, they generally create space for themselves, which minimizes the requirement of the surgeon to retract, either with fixed or dynamic retraction. And here we have ultrasonic aspiration as we approach the medial margin of the tumor. This provides us with an opportunity for subcortical asleep stimulation mapping in this patient. And so as we approach this anatomical margin using neuronavigation as a guide, we can then sequentially stimulate, resect, stimulate, resect, until we reach the subcortical fibers, in this case, associated with distal arm movement. Ultimately, this can lead to a complete radiographic result without any evidence of postoperative ischemia. So approaches to the insuloglioma can be used through transsylvian transcortical strategies. Functional pathways still need to be preserved and stimulated during both strategies. And Zone 2 in particular lends itself to the transcortical route. The rationale for a mapping program is exemplified by cases like that, and also by the host of retrospective studies that have been published over the last 20 years. This study by Philip DeWitt is a meta-analysis of all of those studies and makes two simple points that should be conveyed to our colleagues and to our patients. The first is that stimulation mapping decreases the risk of severe deficits in the long term, and the second is that it also increases the likelihood of greater extent of resection. Achieving a mapping program to meet the ideals of the standard bearers in our field, which are the UCSF program in San Francisco and the Montpellier program in France, is a daunting task that requires methodical diligence as well as a long timeline. These two programs, however, provide examples of the highest ideals that can be achieved, and interestingly, they each achieve these results through their own tailored approach that are somewhat different from each other, including differential use of intraoperative anesthesia, differential use of nasal or oral intubation, different strategies for when to map and in what circumstances to map, and different strategies in terms of the state of the patient during various stages of resection. The intraoperative technology utilization also varies across these programs, whether it be functional MRI, neuro-navigation, use of the operating microscope, use of intraoperative electrocorticography, and the case selections are also varied, including the histologies of the tumors, the sequence of events during the operating room, the utilization of negative mapping paradigms, and the employment of a sleep motor mapping strategies. Nevertheless, each of these programs is capable of adapting their strategy to the case at hand, but on balance, they do have different characteristics in terms of their approaches to intraoperative solution mapping. Interestingly, regardless of these differences, they both achieve exceptional mapping results measured through not only extent of resection, but intraoperative seizure deficits, transient neurological deficits, and permanent neurological deficits. The building blocks for a mapping program are cornered on an effective partnership with neuroanesthesia, a very careful case selection, a mastery of the mapping protocol, and the incorporation of technology when appropriate. At our center, at the Barrow Neurological Institute, we have steadily built a mapping program over 10 years, and during this time, we have varied awake mapping anesthetic regimens in accordance with our neuroanesthesiologists. In the bottom of the screen, you see different sections of each pie representing each neuroanesthesiologist involved in our cases and the number of cases they perform per year, noticing a gradual refinement in the number of neuroanesthesiologists, which reflects the specialization in the field. Intraoperative seizure rates are one of the most important metrics to gauge the success of an intraoperative mapping paradigm and protocol, and at our center, those seizure rates have steadily declined, despite our also steady decline in our use of intraoperative electrocorticography. Asleep versus awake mapping is a careful selection choice that has to be made, in our experience, for obese patients, those with neuropsychological contraindications, significant neurological deficits, or large tumors. Asleep motor mapping is the safer strategy, even though it's quite clear that awake mapping gives you a tighter map. Here we have, over the last five years, the gradual trending of our asleep to awake ratios reflecting this more prudent and likely conservative approach to stimulation mapping strategies. Our center employs a fixed mapping protocol, as this is likely the best way to initiate a mapping program at any center, and enables clear communication with all the members of the anesthetic team with regard to the sequence of events, as well as what to expect next in each stage of the mapping paradigm. Positioning is a critical element of any mapping case, whether the patient is asleep or awake. It's important to keep them in a semi-lateral position with their body neutral in alignment and not completely on their side, wherein that can require an axillary roll. The navigation arm must be placed out of the way so that the patient's face can be visualized and that it still remains outside of the operative field. And we employ a LALA bar in order to drape the patient effectively and take the drape over the LALA bar, cut some of the drape out in a non-sterile fashion so that the patient's face can be easily framed. It's also important to have their contralateral arm out, and ideally without IVs or other encumbrances in it, but carefully padded and free. The neck must be slightly extended and in line with the body so that if an emergent intubation is required, this can be done safely. The sleep motor mapping is very similar in its positioning to awake. And the OR team needs to know not only their roles, but each other's roles. This includes the surgical techs, intraoperative neuron monitoring, any neuropsychologist who is in the case for the awake mapping paradigm, as well as the personnel to deploy our audiovisual recording devices. Rapid electrocorticography can be deployed in select cases to measure after discharge potentials. And in general, at our center, we position the patient awake and then have them asleep for anesthetic pinning. They're then asleep until the craniotomy is completed and the dura is anesthetized. They then are awakened and encouraged to hyperventilate while the dura is closed. And then the dura is opened when the brain is relaxed. We begin with the cortical mapping, then let the patient go back to sleep for resection, and as needed, we'll reawaken them if additional mapping is necessary. Surgical technology can be helpful for mapping cases, and we have had experience with functional MRI. Nevertheless, it's not sufficient to plan regions of tumor resection, as there is too much variability in the specificity of the device. DTI tractography will also give you some better sensitivity and specificity, but nevertheless is not sufficient to make millimetric decisions when it comes to surgical resection of tumors. We employ a combined audiovisual solution to patients with a device that's custom made and enables us to show patients different computer-generated paradigms, visualize their face and record their voice and project that onto operating room screens, so that all of this can be visualized by the surgeon in a single screen in an integrated view in order to take in all of the variables that must be processed during the mapping paradigm. There are a variety of study devices in development, including this one that measures functionality as a function of blood flow following peripheral stimulation through SSEPs. The utilization of motor mapping is best exemplified in cases in or within the motor strip. Here we have a case where the tumor is putatively displacing the DTI fibers laterally. This took us through a contralateral interhemispheric approach, which is done in a lateral position with the neck laterally flexed, a small coronal incision over the sinus, a bifrontal craniotomy and dissection down along the contralateral hemisphere towards the falx, cutting the falx in a right-handed patient from right to left using micro scissors, as well as standard micro dissection techniques, creating a trap door in that falx that flaps downwards, visualizing and then stimulating the contralateral medial cortex, which, despite the tractography, did demonstrate eloquence at 3 milliamps per channel, enabling us to find a non-functional window above that, which we transgressed with direct visualization, and then use a combination of bipolar, electrocautery, micro scissors, ultrasonic aspiration to continuously resect the tumor and then stimulate the functional boundary of the tumor on the backside of the tumor, which also was eloquent. This type of strategy can be easily accomplished and lead to good surgical as well as functional results. The learning curve for stimulation mapping is a long one. In our initial experience at our center, building a program from scratch has led to intermediately successful rates of intraoperative seizures, deficits, transient, and permanent as compared to the 20-plus year experiences of San Francisco and Montpellier. Nevertheless, one can see this learning curve lead to improvement and the trending downwards of all these metrics with, in the most recent year, a 3% intraoperative seizure rate, 5% permanent deficit rate, 7% transient deficit rate. Undoubtedly, this learning curve will continue over the next 10 years, but on balance, an intraoperative mapping program is an essential element of any major brain tumor center and neurosurgical oncologist practice. It does lower neurological morbidity and increases extended resection, but can only be achieved through a multidisciplinary partnership with our neuroanesthesiologists, judicious use of a sleep versus awake mapping, and a very clearly defined mapping protocol that we can communicate it to the perioperative staff and facilitate the institutional learning curve. This learning curve likely requires 10-plus years of programmatic development in order to achieve the sub-2% seizure and morbidity rates reported by San Francisco and Montpellier. So with that, I will conclude, and thank you for your time and attention.

interoperative mapping program

glioma surgery

early intervention

extended resection

low-grade gliomas

fluorescence-guided surgery

genetics and gliomas