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| PERSPECTIVE |
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| Year : 2021 | Volume
: 4
| Issue : 2 | Page : 19-21 |
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Progress on glioma surgery and multimodal treatments
Mitchel S Berger
Department of Neurological Surgery, University of California, San Francisco, CA, USA
| Date of Submission | 01-Jul-2021 |
| Date of Decision | 02-Jul-2021 |
| Date of Acceptance | 02-Jul-2021 |
| Date of Web Publication | 29-Jul-2021 |
Correspondence Address:
Dr. Mitchel S Berger
Department of Neurological Surgery, University of California, San Francisco, CA
USA
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/glioma.glioma_9_21
How to cite this article:
Berger MS. Progress on glioma surgery and multimodal treatments. Glioma 2021;4:19-21 |
Molecular understanding of gliomas has grown significantly in recent years which has improved patient management. Aggressive safe tumor resection, however, remains the mainstay of management globally. Importantly, the definition of extent of tumor resection (EOR), especially for glioblastoma (GBM), has evolved with time. EOR has previously been divided into different degrees, but this is being re-evaluated due to growing evidence suggesting that tumor excision must extend beyond the enhancing border of GBM.[1] Newer classifications of EOR are attempting to define the extent beyond the enhancement into the flair abnormality which can be resected. Similarly, for low-grade tumors, recent evidence suggests that “supramaximal resection” decreases the risk of malignant transformation. Our recent study on GBM showed that resection beyond enhancing tissue in a classic GBM patient, such that <5 cm3 of residual flair signal is left, significantly prolonged survival.[2] The new strategy of the decade, therefore particularly in patients under 65, is to not only remove contrast-enhancing tumor, but when safe and feasible, extend into the flair signal.
Another important step in tumor resection is the ability to adequately assess scans and predict EOR before surgery. This estimation before surgery can influence the surgical EOR. Results from our study showed that with the advance in techniques and technology, neurosurgeons at all levels, especially junior surgeons, are getting better at predicting EOR and residual tumor volume.[3] Following a similar protocol, we attempted to quantify eloquence in GBM patients. We found that the use of imaging alone to determine eloquence resulted in lesser EOR and higher chance of impairment in patients. Glioma surgeons with experience in mapping, on the other hand, make predictions that are more accurate and have better surgical outcomes.[4] It can be inferred from this that inaccurate eloquence predictions based on imaging alone result in expecting more residual tumor, and thus, lead to poorer outcomes. Developing experience in mapping to perform resections is therefore very important.
Other newer tests and techniques that can predict functionality and likelihood of recession are also coming into play. Some teams are using resting functional magnetic resonance imaging to predict connectivity; we have used magnetic source imaging with magnetoencephalography to determine connectivity maps using different kinds of tests like syntax and auditory naming. Magnetoencephalography is used to create mathematical models to predict highly connected or functional tissue based upon the activation amongst different regions. This strategy enables us to predict the duration of postoperative deficits based upon a decline in auditory naming and syntax function in patients who had resections in functional negative mapping areas.[5] From this, we can understand that the future of mapping is going to be dependent on not only intraoperative stimulation mapping but also on connectivity maps preoperatively determined.
Transcranial magnetic stimulation (TMS) is another important strategy with growing applications in surgery. TMS enables stimulation through the scalp to identify motor and language areas which can then be registered on magnetic resonance imaging scans. This gives a good understanding of where functional tracks are located and can serve as reference point during cortical and subcortical stimulation.[6] TMS can also be used in predicting plasticity. Often tumor resections have to be stopped due to detection of function on mapping. In such patients, surgeons can use TMS on follow-up visits to track shifting of function or plasticity to plan secondary surgeries or treatment plans. Perhaps the most important application of TMS was recently discovered. A group from Germany recently showed that contralateral application of TMS daily for a week (15 min/d) in patients who developed postoperative motor deficit resulted in significantly greater recovery than in patients who did not receive TMS.[7] The assumption is TMS helps reorganize pathways by activating rehabilitation. This is an exciting finding, and we have started to investigate this further. We also recently did a study that proves plasticity in the motor cortex is real.[8],[9] Use of magnetoencephalography showed results supporting plasticity in the cortex but not in the subcortical system-white matter.[10] This means, during surgery, injuring the subcortical pathway results in permanent deficits.
Other techniques that have important applications in surgery include navigational ultrasound, which can be used to identify optimal corridors to subcortical tumors just underneath the normal cortex in the motor system. The use of this creates a chance for tumor resection without injuring motor tracks. There is also the technique of inserting diffusion tensor imaging tracks preoperatively on imaging and applying this information intraoperatively before even starting mapping. Many surgeons use this information intraoperatively for reference with mapping. Intraoperative magnetic resonance imaging is another important equipment in surgery; the endoscope, on the other hand, in our experience, is not particularly useful and has minimal impact on glioma surgery. The Raman spectroscope permits us to see pathology within minutes of doing a biopsy in the operating room, and now an artificial intelligence program is being developed that can scan tissue and immediately make the diagnosis. This will eventually happen at single-cell level and play an important role in personalized medicine.
We have over the years investigated many interventions that can be safely performed using brain mapping. We observed that there are variations between patients who learn different languages at different points in their lifetime. The earlier a language is learnt, the more likely it is to have a great deal of variability for the same task, such as syntax, auditory naming, and for most cortical mapping tests we do. We have shown this before by looking at the probability of finding speech arrest versus naming in areas we know are exactly based upon mapping and stimulation.[11],[12],[13],[14] Therefore, unlike motor function, visual function and sensory function, language function is variable at the cortical level and even at the subcortical level. Based on our experience of nearly Two thousand awake mapping cases, we can confidently say that awake mapping significantly decreases deficit rates by at least two to three times.[15]
The next important question relates to predicting the duration of postoperative deficits. To investigate this, we are analyzing postoperative diffusion tensor imaging and diffusion-weighted imaging for differences. Diffusion tensor imaging tracks around the area of tumor resection are quantified based on the extent of injury from either surgery or ischemia. An index that can predict the likelihood of recovery based on this data is being determined.[16] We believe that by quantifying the limbs of these tracks, the proportion of resection that can result in a permanent deficit can be determined. This emphasizes the importance of subcortical mapping. Examples of tumors that often require both cortical and subcortical mapping are tumors in the middle frontal gyrus. In such cases, situations also arise where cortical mapping is negative versus the subcortical area. We found that the negative cortex can be resected as long as injury to the subcortical pathway is prevented. This results in transient deficits which resolve over 1–3 months.[17]
For awake brain mapping, a number of tests exist and more are being tested. For frontal, temporal and insular lesions, we recommend using motor function tests and language function tests including speech arrest, picture naming, and reading tests. For parietal lesions, we use line bisection tests, somatosensory tests, and calculation tests. By using these tests alone, we found that our deficits remain around 3%.[18] The subcortical system is mapped based on a study in which we determine ventral versus dorsal pathways based on a picture-word interference test where a patient is shown pictures with words and asked which words are related to the picture. During this test, if a patient can carry out the task correctly while stimulation is applied, we know that the ventral stream (inferior fronto-occipital fasciculus) is not being hurt. If during the test the dorsal stream (arcuate fasciculus and superior longitudinal fasciculus) is stimulated, we get phonological paraphrasing.[19] Other teams use a more complex set of testing. Hugues Duffau has a task for testing almost every brain cortex function in various brain regions.[20] Jinsong Wu's test strategy is similar to ours but with a few more tests.[21],[22]
To map motor functions, we now use the triple motor mapping technique-a combination of TMS, bipolar and monopolar probe. The bipolar probe is also used because it has the advantage of using low frequency, with a concentrated current density between its tips a few millimeters apart.[23] By using this technique, we recorded only one mild motor deficit in the cases we reported. Bipolar stimulation mapping, is, therefore, also good for subcortical motor localization because the monopolar probe carries a risk of 10+% risk of a permanent deficit although being more sensitive than bipolar in terms of distance mapping. Lorenzo Bello has published comprehensive articles on motor mapping explaining his strategy of doing motor mapping asleep using the monopolar probe to get the best accuracy.[24] He reports that doing it awake with low frequency is overly sensitive causing movement, which consequently results in decreased tumor resection compared to doing it asleep using both high and low frequency.
We have witnessed that a lot has been done to manage low-grade gliomas over the last decade, with many new trials being performed. Isocitrate dehydrogenase inhibitors are being tested with evidence showing they delay progression.[25] Isocitrate dehydrogenase vaccines are also being investigated with their effectiveness results still pending. GBM, however, remains a tough disease with relatively short survival and yet the standard of care has not really changed in the last 5 years. We treat this disease with surgery, radiation, and temozolomide. The only variation in approach is mostly dependent on methylation status of O6-methylguanine DNA methyltransferase. For recurrent cases, lomustine-an alkylating agent and the same drug for over 30 years, is being used Avastin or bevacizumab is also used in recurrent cases with the response rate ranging from 6 to 9 months. These agents are used in conjunction with surgeries and in cases where survival extends beyond 3 years. Going down this pathway, a good job at sequencing tumors and finding the molecular targets has been done but in reality, little progress has been made.
Researchers are also now investigating metabolic inhibitors such as isocitrate dehydrogenase inhibitors and nicotinamide phosphoribosyl-transferase inhibitors. A lot of targets have been tried, such as B-Raf proto-oncogene serine/threonine-protein kinase, epidermal growth factor receptor, mammalian target of rapamycin, vascular endothelial growth factor, phosphatidylinositol 3-kinase,[25] yet the response are not very durable and response rates remain around 5%–15%. Trials with second- and third-generation targeted therapies are ongoing, but presently none looks very promising. There have not been a lot of phase III clinical trials, because phase I and II results were not satisfactory. Interestingly, in younger patients with high-grade midline tumors with histone mutations, using the new drug ONC201, which affects DNA damage repair, is showing promise.[26] There are also a number of ongoing immunotherapy trials looking at a combination of checkpoint inhibitors and other agents like temozolomide or vaccines in an attempt to enhance the immune system or reverse immune suppression. In this category, chimeric antigen receptor T-cell therapies that alter T cells to target two or three points on GBM cells look exciting.[27],[28] A lot of resources are being focused on glioma research, and we believe slow yet steady progress is being made toward the management of this disease.
This manuscript was prepared by N. U. Farrukh Hameed, Department of Neurosurgery, Huashan Hospital, Fudan University, China based on the presentation of Mitchel S. Berger.
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