Interactive Transcript
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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.
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