 Now we'll shift our gears and talk about the overall things that the clinicians and to some extent the radiologists are also supposed to be aware of. These will be what is the presentation of tumors and what are the causes of tumors, what are the predisposing factors of tumors, how we approach tumors, how we treat them and what are the outcomes of the treatment and what we are supposed to look at it. So these are the things that overall, as such it is an idiomatic thing, but these are the things that are associated with increased risk of brain tumors that will be exposure to wine and fluoride, eepstein bar wires and these are the syndromes like NF1, tuberous sclerosis and just think I don't even know how to pronounce it and Tucker syndrome and they bought basal cell carcinoma syndrome. So these are the syndromes that will predispose those patients will have a higher incidence of tumors. They have these genetic changes you would think of all the white matter changes to be less or likely high hematomas and more likely to be predisposing higher incidence of tumors and that. So how did they present the mainly the presentation what typical I have seen of the patients they generally come in with the chronic headache, visual changes or seizure the first presentation of seizure they come to the emergency room and then we find out that there's underlying brain disease on MR it turns out to be brain tumor. But the presentation will be to a great extent dependent on where the tumor is located. So if it is in the frontal lobe they will kind of present with the frontal lobe syndrome. If it is close to the Sylvian Fisher it will present with speech changes if it is in the occipital lobe it will present visual changes if it is in the parietal region frontal parietal adjacent the motor cortex he'll have sensory or motor abnormalities. So these depend if it is in the brainstem it will present with brainstem symptoms posterior for certain to be presenting sooner than later the supertentorial tends to present with seizures infratentorial does not tend to present with seizure. So those are the things depending on what kind of tumor how aggressive it is and what is the location of it and by the time it is presenting what is the size of it and how much of mass affected it is causing those are the things that decided its presentation. But by far we talked about the location having those typical symptoms and presentation they present with headache nausea vomiting and vision speech hearing changes or seizures. These are the most common presentations that the tumor will present with. Next what do we do with these how do we diagnose them so the basic thing for W.H. classification would be the histology of the electron or light microscopy that would be the first step of classifying that and after that for the nomenclature. The second step would be to do immunohistochemistry cytogenic and genetic analysis and name that as the second part of the tumor name. So we talked about putting in the IDH mutant or not mutant we talked about TRT we talked about real status we talked about P53 status we talked about MGMT status we talked about co-deletion. So those are the nomenclatures that you will add to it that will you'll get by genetic and genetic analysis and immunohistochemistry. So these are the tests that you will be doing in the brain tissue. So what are the factors that affect the overall prognosis of the tumor. Most important thing is where is the tumor located and what is its aggressiveness. So if the tumor is situated in a very, very important or eloquently or say brainstem. It is almost that the patient cannot be treated because of that either the treatment will be more harmful than the cure the patient will die or have a major motor deficit or some major function deficit. So it is it is very poor prognosis. The other thing is the grade of the tumor the grade one is very good in response the grade four is very poor response. Then we talked about all the chromosomal markers the IDH mutant is a good response the co-deleted is a good response the P53 increased expression is a good response. The TRT is a poor response ATRX is a good response. So we talked about those the genetic markers they will be decided. Then after that what how much of tumor is left after surgery if you could do surgery if it was an eloquent area and we could only do debulking the tumor is still there it will immediately recur so that will be a poor prognosis. So all these things these are characteristics of the brain tumor that decide. But on top of that if the patient has a very good tumor say in the frontal lobe or low grade WHO one IDH mutant co-deleted oligodendroglioma in the frontal lobe but the patient's health is miserable. He has immuno compromised status he has asthma he has diabetes he has cardiac disease he has all possible illness he has intestinal resection he had Crohn's disease ulcerative colitis and whatever the patients overall general health is poor. It is almost as if he has got a death sentence you cannot treat in that patient. You cannot give him chemotherapy you cannot give him radiation therapy you cannot do he cannot undergo surgery his physical status. So this this is one important thing that we tend to overlook that all of the things may be favorable as far as the tumor is concerned but as general health is poor then then the outcomes may be poor. Next we move on to the staging system for thank God by love of God we don't have a staging system in brain tumors otherwise that would be another thing that we would have to know. So by far there is no clear staging system it is just the WHO staging system and most of the time in my 15 years of practice I have only seen one tumor like a GBM going out of the brain and going into the bone which was a very very unusual tumor. Otherwise by far they're localized into the CNS system. The most they can do is tumors like medial blastomas and epinepumas corot pexus papillary carcinomas they can do is metastatize it on the neural axis but they tend to stay within the CNS. So that is by far the classification of the staging that is all we have to cover we really don't have to do a general body pex scan or look for metastasis here and there from brain tumors. Then what are the factors that we take into account to treat tumors again it is we talked about that the histology one through four classification that is the thing that is deciding how the outcome is how the treatment will be based the second is genotype of the cell. So the main WHO classification the first histology the second is being the genetic code of that tumor. Those are the two main things that decide how the treatment will be based how the outcomes will be how we will treat it after surgery and treatment how the tumor will respond. And the other things that decide is where the tumor is located in the brain how much close it is to eloquent area and how much of the cancer is left after surgery. So those are the things that also matter how the outcome was treatment. So what do we use for treatment one is surgery second is radiation therapy that can be focal radiation therapy like radio surgery or IMRT or it can be a total brain radiation if the tumor is spread over a very large area. Then we have chemotherapy then we have immunomodulation immunotherapy targeted therapy those are the things that we use. So we will just briefly go through that surgery again as any surgery anywhere you see something abnormal you take it out if you cannot take it out stick it somewhere close by. That is the principle that has been for surgery whether it is abdominal chest or brain surgery that is the same concept. The only thing in the brain tumor you have to be careful of is you have to make sure that you are not affecting the eloquent areas of the brain. Important areas important white matter tracks these are not affected and you do few tests of that to make sure that these parts are not affected and I will just go through briefly by the end of this lecture for that. The other things that we talk about is the chemotherapy. So there are different chemotherapy agents there are kindness inhibitors which stop cancer cells from reproducing and decreases their blood supply. Then there are the VGF inhibitors or vascular endothelial growth factor which promotes tumor genesis or increases the blood supply and the nutrition to the tumor you have agents that suppress the blood vessels that feed the tumors and their permeability. So the evastin being the one that is most common but this is associated with a false sense of safety. But this is one of the most commonly used drugs also at the same time. Then you have alkylating agents which adds methyl groups and stops the DNA from replicating and cells from replicating. Then you can have temzolamide which is DNA replication inhibitor and then you can use combination of that which the most common being PCV or procarbazine hydrochloride lomastin. These are bunch of alkylating agents basically adding methyl groups and preventing DNA replication and therefore preventing the tumor genesis of that or decreasing the growth of the tumor. So these in combinations are separately but by far the names that you will hear most would be evastin, temzolamide, lomastin and procarbazine. These are the names that you will most frequently hear from the oncologist and the way they act is we talked about this alkylating agent acts methyl groups. So this depends on the MGMT, the promoter gene hypermethylated or unmethylated whether the DNA will be able to respond. So again, do these don't matter? By and large when we look at the images of the radiology they don't matter but when you are talking about how to treat the patient when there's an interdisciplinary conference and the neurosurgeon and the neuro-oncologist is breathing down your neck and there are 20 people sitting in the same room and they ask you is this a recurrent tumor? Am I supposed to go in and do surgery? Is this pseudo-progression? Is this pseudo-response? That is the time you're supposed to take all the information. You find out what was the tumor agent that was given to that for treatment? What was the patient's genetic code? What was the tumor associated? So you gave a patient alkylating agents a temzolamide. You gave a patient who was unmethylated. Now that's not going to affect that patient. So you see changes in the brain after surgery and after treatment. Chances are this is a recurrent tumor. Whereas you gave temzolamide to a hyper-methylated patient. Chances are you completely treated that suppress the tumor and immediately in the near future post-treatment. If there are any changes in the surrounding brain pattern, that's more likely to be tumor treatment related rather than recurrent tumor. And you would hold back with an acrylcine. So that is why we are supposed to know what chemotherapy, how it acts and what is the genetic code tumor. This is a patient who was given chemotherapy. So this was a brain tumor, which initially showed some progression, but later on, involuted. And there's very little bisect surrounding white matter changes again as opposed to what you would see with radiation therapy. Next is you can use targeted therapy and into this falls that you've asked and where you're specifically going after factors that help tumor growth or something that is helping the two cells multiply. And then you suppress that factor. So you can go after specific antibodies or the receptors of the cell. Those are the things that you can do. It's common that you use for this is evastin where this is prevents the VEGF or vascular endothelial growth factor, which basically prevents new vascularity, reduces the effectiveness of gap junctions and creates fenestration and endothelium of existing brain capillaries. So all involved when you give the evastin, it looks as if you have involuted the tumor, the whole tumor just disappears. But it is a very, very false sense of safety that you're getting with this VGFB. You have to monitor it very, very closely. There are a few downsides. The most important being the pseudo response that you feel is false sense of response that the patient is invioluting, whereas it is actually not. Then the other thing is a patient who has already had hemorrhage is not a candidate for this. And the patient perfusion imaging becomes kind of unreliable in patients who have received evastin or VEGF inhibitors. And as such, perfusion is generally very unreliable in patients who have had hemorrhage in the past. So these are the downsides of getting evastin to the patient. And then also, once you start the patient on evastin, they get thrown out of a lot of clinical trials. So that is another issue that we encounter. They cannot get new research medications. So this was a patient who was started on evastin. You can see a GBM, which is intensely enhancing. This almost shows that it disappeared, the tumor disappeared and invioluted. But actually, if you see this was a pseudo response, the tumor was this before treatment and it has progressed overall. So this was the issues that we run into. Next is you can have immunomodulation where basically we understand that tumors are mainly because of patients' immunity being suppressed. So you can either boost their immunity or restore their immunity by vaccines and those things. Those are the other things that we are currently mainly in research trial, but are being used at our institution to repaint tumors. So this was a patient who was saturated with immunotherapy and initially progressed, but then later on it invioluted. The same thing with enhancement, the same which is over the period of time where you see the patient has overall to have a good response. And then you, of course, you give supportive care where you give steroids to decrease brain edema, they're nausea, vomiting headache, all these things respond with that. And then you give them anti-epileptic. There are tests we talked about that should be done before any intervention to identify the eloquent areas. So one of them is rather the most important of them is the functional MRI, where we use the bold technique to see the areas that have increased oxygen supply during activation. Whenever brain does a function, there are two ways there is nutrition increased to that part of the brain. One is vasodilation and the second is increased extraction. So the blood vessel from here to here gets dilated and then there's increased number of oxygen that is extracted. But one of the things that is different is the vasodilation is significantly more than the amount of extraction. So this is a normal state where you are supplying four oxygen and two oxygen. This is the arterial side and this is the venous side where two oxygen are remaining because of two oxygen being extracted. Now you make the patient do a function, you supply vasodilation, it multiplies by five times. So you have 20 oxygen being supplied and only extraction doesn't increase the same amount. So says five, arbitrarily say five oxygen come out, you are left with 15 oxygen. Now this is the ratio we want to do when you're doing the bold technique or comparing the function and giving the red color to that area of activation. If you do it on the venous side, you have a ratio of one is to five. I mean, on the arterial side, you'll have a ratio of one is to five approximately. And on the venous side, you end up with a higher ratio. So you want to see the comparison on the venous side and that is the side you calculate for. So this was a patient of polygodendroglioma, calcification, low grade tumor, narrow zone. This is the functional task where we did the motor and the language which consists of rhyming, word generation, listening task. And then this is the brain mRNA overlap with the function. Now here the motor task is distant from there. Now you need a gap of at least five millimeters to be completely safe during surgery. Whereas in language tasks, this is coming too close. This is almost less than five millimeters. And here it is almost overlapping on rhyming tasks. So if we take out a good margin, a clear margin of the tumor resection, he will end up with some deficits. So these are the things where you only do debulking of the tumor. So this is the issue that you run across later on. Visit completely accepted. This is what decides the performance of the tumor. The second thing that we do is the diffusion tensor imaging. Now this is something in research. This is not something billable. This is not something that you can defend in court of law. But this is frequently done to mark the white important white matter fibers where we use the diffusion technique. Like if you do it for diffusion technique, you do it two dimensional for stroke where you see the random motion. But all these random motion of molecules of water, but all these motion of molecules is finally directed along the white matter tracks. So this is what you're calculating along the Z axis. Also the third axis you are taking into account. And then you color coded to identify which are these are the most important, the archway fibers and the corticospinal tracks. These are the most important tracks that you identify. Now what pictures we give these pictures that we give to the clinician have no importance. They take this software, the digital information feed into to their own software during surgery, which is what they use to decide whether how close to the white matter fibers they are, what how close to the archway or corticospinal track fibers they are or visual track they are to before while they're surgery. Then the other thing that we do is a perfusion imaging. Now this is the same way what you use for strokes. You do the same calculation, the four parameters. The one we use for tumor is the area under the curve with the cerebral blood volume. So this is a tumor which is within the frontoparietal lobe has enhancement. So it's a grade three or grade four by imaging. And given its narrow zone of transition, we can talk about the IDH and all those things. But clearly this is not what we'll be talking about when we are giving out the diagnosis. But what is we are talking about here is the perfusion. There's intense elevated CBV in this tumor. So this is a kind of an aggressive tumor. This is perfusion imaging is what you will look for even when you are confused between radiation accrosus versus recurrent tumor. The recurrent tumor will have elevated CBV. As a physician, we all know what to do to treat a patient, but it is equally important for us to know what not to do to the patient because sometimes the cure can be more harmful than the disease itself. So when should we not operate on a patient? So if it is a low-grade tumor with all the nice characteristics like IDH mutant, co-deleted, TERT negative, ATR expressance, increased expression of P53 and MGMT, hypermethylated, all those things are present. And it's located in the frontal neoplasm far away from any eloquent area, not causing significant symptoms. Incidentally noted, patient came in with a trauma and we first saw the neoplasm. You don't need to operate that. You don't unnecessarily need to go in so that you will not want to operate. Then the flip side of that is if it is involving an important area, eloquent area, say completely involving the insular cortex or completely involving the motor cortex or the brain stem, you operate one of those that you give him a debilitating condition that is not just not worth it. He will live for five years with complete paralysis as opposed to you give him one year with completed retention of function, that is better. So this is finally between the patient and the clinician to decide. But those are the things where you do not operate. Then patients in overall poor health and poor compliance, those ones you tend not to operate. Then if there is, you change your treatment from aggressive surgery to radio surgery if there is less than two millimeter gap from important structure. So those are the things that you want to keep in mind for treatment. Talking to the neurosurgeon or the neuro oncologist, you will hear these terms that, oh, I was doing the surgery and then I got, I felt it was a bit too dangerous. And I stopped at this point. So, and then you see there is a residual tumor. So what made the surgeon stop at that point? These are the things that these are the four things that they use to decide when to stop. We talked about functional imaging, how close it is to the eloquent area. If it is overlapping, they debulk the tumor, they don't take out the whole tumor. That they use then the DTI, not the images. We give them the information that we give the digital information into their own software. And then they decide on that how close the white matter tract is to that and accordingly they operate. And the other, the two most important thing are these two where there's an electrophysiologist actually in the surgery room where they are stimulating the white matter tract and looking for a response in the distributing muscle by EMG or the other way around either side. They can give a stimulus distally and see how it is coming to the white matter tract that they're operating. And this is where they know that they're getting to a very important area and they stop the surgery at that point. And lastly, sometimes the patient is awake answering the questions doing tasks during surgery and that is what when they see something changing, they stop at that point. So these are the four or five things that the surgeon takes during the OR to see how they can do for surgery. Lastly, we will talk about what we do for residual tumor. We talked about how do we identify with the residual tumors with the genetic code of that patient, what agent we use for treatment, the things that we talked about earlier. But immediately after surgery, if there is some tumor left, then you can either use new adjuvant chemotherapy or you can gamma knife that area or you can start him on research drugs, clinical trials. Those are the things immediately later on, if there is a tumor that comes back or residual tumor, you can either repeat surgery or you can use radiation surgery or you can use evastin. So this is the approach that the clinicians use with whatever is left after initial treatment. These are the most important things that we are supposed to know about tumors before we talk about tumors. The most important thing that I want you to take back from this lecture is the five molecular markers, IDH, P53, co-deletion and NGMT, hypermethylated and ATRX having a good prognosis, TERT having a poor prognosis. That and that alkylating agents use methylation as DNA harmful. I mean, harming the DNA so that we can kill the tumor cells. And that keeping in mind that evastin makes profusion imaging poor after treatment with that or under libel and the fact that you have to keep in mind about pseudo response that the tumor is actually going and not actually treated in a patient with evastin. So these four or five things you have to keep in mind if you are actually involved in tumor treatment. Thank you very much.