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BRAF and H3K27 Gliomas

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So, in this short presentation,

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I'm going to be talking about BRAF

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and H3K27 mutant diffuse midline gliomas.

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And this review article very clearly shows how

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adult gliomas and pediatric tumors arise

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from progenitor cells.

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For example,

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most of the adult diffuse gliomas,

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they are IDH mutated or IDH wild type.

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For example, they have third or EGFR mutation.

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On the other hand,

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majority of the low-grade pediatric tumors are

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BRAF driven and that's what we're going to

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be discussing now.

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So BRAF mutation,

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it leads to activation of MEK pathway,

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independent of the extracellular factors,

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leading to oncogenic transformation, and hence,

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excessive cell proliferation and survival of these

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tumor cells leading to tumor growth

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and tumor production.

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This analysis showed very clearly that majority

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of the lower-grade pediatric tumors,

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they are either BRAF mutated or BRAF fusion.

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So, they are kind of BRAF-driven tumors,

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more than 50%, as you can see from this distribution.

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This is an example, you know,

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a young patient,

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25-year-old presenting with headaches,

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has a very innocuous-looking mass in the

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inferolateral left frontal lobe over here.

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You, in fact, can even see some scalloping of the bone.

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Again, seen over here on the coronal view.

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And if you look at the MRI,

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this is very classic soap bubble

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kind of cystic lesion,

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multiseptated cystic lesion in the

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left inferolateral frontal lobe,

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majority of the tumor is in the subcortical

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and the deep white matter.

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And this is classic for a Dysembryoplastic

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Neuroepithelial tumor, DNET,

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which are majority of them, as we know,

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are BRAF-driven tumors.

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Other common lower-grade tumors which have BRAF

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mutation or fusion, are our, of course, you know,

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a DNET over here.

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Another example of pilocytic astrocytoma,

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cystic lesion with the mural nodule.

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Another example over here is ganglioglioma,

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and majority of these BRAF gliomas occur in

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young patients, presenting with seizures,

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usually cortical-based tumors

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with cyst and mural nodule.

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That's classic examples of BRAF-driven tumors.

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This is another example, you know,

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of a pilocytic astrocytoma,

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had a BRAF fusion in a young 12-year-old male

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patient. And this is just to show you, you know,

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this is 2008 when the tumor was diagnosed

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and 2018, post-treatment,

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you can essentially cure these tumors if you do a

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complete resection and this is what happens in a

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case like this, you know, they have good survival.

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Not all of them are lower grade,

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a few small percentage of BRAF gliomas in

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pediatric patients or young adults,

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they could be grade three, for example,

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a pilocytic xanthoastrocytoma over here.

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Another patient who actually had almost a grade

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four of GBM, but was a BRAF-driven tumor.

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One of the things which has happened in the last

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few years is we know that based on

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these genomic markers, again,

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showing you that example of a PXA grade three

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tumor which underwent a subtotal resection

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because of its deep location,

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came back histology as WHO grade three.

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This tumor would have been treated with standard

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chemo regimen just a few years

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back but not anymore.

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Because this is again a BRAF V600E fusion

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mutation. And that is the reason, you know,

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our neuro-oncologists now treat these tumors with

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a combination of anti-EGFR and MEK inhibitor.

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And this is what happened six weeks later,

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within six weeks,

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the tumor shows quite a significant response and

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this is the power of genomics in gliomas.

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As you can see that you have targeted therapies,

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not for all kinds of all subtypes of gliomas,

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but for some of them,

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this is the other example I mentioned

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of another young patient,

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21 years old presenting with a solid enhancing

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very vascular mass. In fact,

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we did a catheter angiogram,

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and it almost looked like an AVM.

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Because of the so much vascular. Here,

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we have the functional MRI with tractography,

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showing you the relationship of the tumor with the

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corticospinal tracts. And this one came up,

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came back as an oligodendroglioma BRAF V600E

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mutation. And this is post-baseline.

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You have complete resection of the tumor,

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but this tumor came back very quickly within a

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year or so. You know, the tumor was back again,

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as a recurrence, you know,

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a similar kind of solid enhancing mass.

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At this time,

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the patient underwent another surgery and now is

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treated with this anti-EGFR and MEK inhibitor

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combination therapy, and this is two years later.

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The patient is actually doing rather well. Now,

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the second category I want to talk about is these

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H3 K27 mutant diffuse midline gliomas.

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A young patient,

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a 14-year-old male who presented with headaches

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and there is a tumor in the right thalamus causing

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some mass effect and hydrocephalus,

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but the tumor actually looks fairly

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low grade or benign tumor.

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Not anymore, you know, within two months,

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the tumor started to explode almost,

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you can see an increase in size.

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There is new areas of enhancement

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within the tumor,

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and that's the time the patient

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underwent subtotal resection.

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The pathology comes back as an anaplastic

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astrocytoma grade three. However,

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this is clearly not behaving like an anaplastic

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astrocytoma. And the reason for that, as we see,

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this unfortunate child ended up developing

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extensive leptomeningeal metastasis within a year

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and dying from this tumor and

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the metastatic spread. And,

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the reason for that is because these are

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H3 K27 mutant diffuse midline gliomas.

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And actually,

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you can see on the baseline MR spectroscopy

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clearly showing that the tumor is very

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aggressive despite no enhancement,

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you can see the high choline-to-NAA ratio and very

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low NAA peak suggesting that this is a very

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cellular and proliferating tumor.

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Another example over here in a young patient,

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a 15-year-old presenting with headache and

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vomiting. We have a mass in the right thalamus,

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which is also showing some areas of restricted

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diffusion, some solid enhancement.

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But more importantly,

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this patient actually presented with

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leptomeningeal extensive diffuse leptomeningeal

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spread at the initial onset.

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You can see the diffuse leptomeningeal

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enhancement,

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not just in the brain but also in the spine.

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There is sugar coating of the spinal cord

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and this, this is again, you know,

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another example with H3 K27 mutant diffuse midline

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glioma which will present either

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at initial presentation,

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not that common but eventually will spread with

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leptomeningeal metastasis and usually have poor

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prognosis. And these are different examples.

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Again, you know, children or young adults,

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midline or paramidline masses,

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usually clinically symptomatic poor

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prognosis that's very important.

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And the majority of them will have leptomeningeal

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spread and eventually will have a high mortality

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because of the tumor spread because of the

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leptomeningeal spread. Different examples.

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Another one in the brain stem over here,

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We do see a few cases in the spinal cord,

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as you can see one tumor over here in the spinal

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cord GBM which turned out to be H3 K27 mutant.

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Another one in the Corpus medius, right?

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These are again, same cases,

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you can see younger patients, young adults,

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A spinal cord GBM and A lesion in the cornu medius

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both turned out to be H3 K27 mutant.

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That is one of the reasons, you know,

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because of this marker and the poor prognosis

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associated with this subgroup who came up in 2016

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and classified these tumors actually as a separate

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entity as you can see from this 2016

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WHO classification update.

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And this study clearly shows why these

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tumors should be grouped separately.

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This is a study looking at pediatric GBMs and you

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can see IDH Wild-type GBMs even in pediatric age

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group doing much worse than the IDH mutated

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GBMs as we know from the adult population.

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But look at the K27 mutant

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diffuse midline gliomas,

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they are actually even worse than IDH wild-type.

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Looking at the survival. Now, here,

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here is another example, a patient who had,

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in fact,

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a little older in which is slightly unlike you

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know what we see typically with

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H3K27 mutant midline gliomas,

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at the K27 mutant midline gliomas,

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you have a non-enhancing infiltrative lesion in

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the left thalamus paramidline midline location.

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This tumor was watched because of the innocuous

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appearance and then started to increase in size

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and also high blood volume on the perfusion maps

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as you can see in 2015. And at that time,

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the patient undergoes biopsy comes back as H3K27

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mutant diffuse midline glioma undergoes

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standard stoop regimen.

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And this is three months after the stoop regimen,

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the lesion,

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the enhancing part of the lesion starts

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to increase in size. However,

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the blood volume was not very high

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except at the periphery,

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which is slightly lower than the baseline.

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And this was thought to be a pseudoprogression at

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that time. And this is what happened, you know,

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a couple of years later. Now,

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the patient actually is doing relatively well

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with Avastin and standard stoop regimen.

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And this is six years later, as you can see,

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you know,

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the primary tumor site is still under control.

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The patient has lost a lot of brain volume because

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of the treatment and other things. But you know,

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not all of them,

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some of the diffuse midline gliomas,

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especially if they are BRAF mutant.

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They can do actually a little bit better

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than the garden variety, H3K27 mutant

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diffuse midline gliomas.

Report

Description

Faculty

Rajan Jain, MD

Professor of Radiology and Neurosurgery

New York University Grossman School of Medicine

Tags

Pediatrics

Oncologic Imaging

Neuroradiology

Neoplastic

MRI

CT

Brain

Angiography

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