0:00

So, in this short presentation,

0:03

I'm going to be talking about BRAF

0:05

and H3K27 mutant diffuse midline gliomas.

0:09

And this review article very clearly shows how

0:15

adult gliomas and pediatric tumors arise

0:19

from progenitor cells.

0:20

For example,

0:21

most of the adult diffuse gliomas,

0:24

they are IDH mutated or IDH wild type.

0:29

For example, they have third or EGFR mutation.

0:33

On the other hand,

0:34

majority of the low-grade pediatric tumors are

0:37

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

0:40

be discussing now.

0:42

So BRAF mutation,

0:44

it leads to activation of MEK pathway,

0:48

independent of the extracellular factors,

0:51

leading to oncogenic transformation, and hence,

0:56

excessive cell proliferation and survival of these

1:00

tumor cells leading to tumor growth

1:02

and tumor production.

1:04

This analysis showed very clearly that majority

1:09

of the lower-grade pediatric tumors,

1:11

they are either BRAF mutated or BRAF fusion.

1:15

So, they are kind of BRAF-driven tumors,

1:17

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

1:22

This is an example, you know,

1:24

a young patient,

1:25

25-year-old presenting with headaches,

1:28

has a very innocuous-looking mass in the

1:31

inferolateral left frontal lobe over here.

1:33

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

1:37

Again, seen over here on the coronal view.

1:40

And if you look at the MRI,

1:42

this is very classic soap bubble

1:44

kind of cystic lesion,

1:46

multiseptated cystic lesion in the

1:49

left inferolateral frontal lobe,

1:51

majority of the tumor is in the subcortical

1:55

and the deep white matter.

1:57

And this is classic for a Dysembryoplastic

2:00

Neuroepithelial tumor, DNET,

2:02

which are majority of them, as we know,

2:06

are BRAF-driven tumors.

2:07

Other common lower-grade tumors which have BRAF

2:12

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

2:15

a DNET over here.

2:16

Another example of pilocytic astrocytoma,

2:19

cystic lesion with the mural nodule.

2:22

Another example over here is ganglioglioma,

2:25

and majority of these BRAF gliomas occur in

2:29

young patients, presenting with seizures,

2:31

usually cortical-based tumors

2:33

with cyst and mural nodule.

2:35

That's classic examples of BRAF-driven tumors.

2:39

This is another example, you know,

2:41

of a pilocytic astrocytoma,

2:43

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

2:47

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

2:50

this is 2008 when the tumor was diagnosed

2:53

and 2018, post-treatment,

2:56

you can essentially cure these tumors if you do a

3:00

complete resection and this is what happens in a

3:03

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

3:06

Not all of them are lower grade,

3:09

a few small percentage of BRAF gliomas in

3:13

pediatric patients or young adults,

3:15

they could be grade three, for example,

3:18

a pilocytic xanthoastrocytoma over here.

3:21

Another patient who actually had almost a grade

3:24

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

3:28

One of the things which has happened in the last

3:31

few years is we know that based on

3:34

these genomic markers, again,

3:36

showing you that example of a PXA grade three

3:40

tumor which underwent a subtotal resection

3:42

because of its deep location,

3:44

came back histology as WHO grade three.

3:48

This tumor would have been treated with standard

3:51

chemo regimen just a few years

3:54

back but not anymore.

3:56

Because this is again a BRAF V600E fusion

4:01

mutation. And that is the reason, you know,

4:04

our neuro-oncologists now treat these tumors with

4:07

a combination of anti-EGFR and MEK inhibitor.

4:11

And this is what happened six weeks later,

4:14

within six weeks,

4:15

the tumor shows quite a significant response and

4:19

this is the power of genomics in gliomas.

4:22

As you can see that you have targeted therapies,

4:26

not for all kinds of all subtypes of gliomas,

4:29

but for some of them,

4:31

this is the other example I mentioned

4:34

of another young patient,

4:36

21 years old presenting with a solid enhancing

4:39

very vascular mass. In fact,

4:41

we did a catheter angiogram,

4:43

and it almost looked like an AVM.

4:45

Because of the so much vascular. Here,

4:49

we have the functional MRI with tractography,

4:51

showing you the relationship of the tumor with the

4:54

corticospinal tracts. And this one came up,

4:56

came back as an oligodendroglioma BRAF V600E

5:00

mutation. And this is post-baseline.

5:05

You have complete resection of the tumor,

5:08

but this tumor came back very quickly within a

5:11

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

5:15

as a recurrence, you know,

5:16

a similar kind of solid enhancing mass.

5:18

At this time,

5:19

the patient underwent another surgery and now is

5:22

treated with this anti-EGFR and MEK inhibitor

5:25

combination therapy, and this is two years later.

5:29

The patient is actually doing rather well. Now,

5:34

the second category I want to talk about is these

5:36

H3 K27 mutant diffuse midline gliomas.

5:39

A young patient,

5:41

a 14-year-old male who presented with headaches

5:45

and there is a tumor in the right thalamus causing

5:49

some mass effect and hydrocephalus,

5:50

but the tumor actually looks fairly

5:52

low grade or benign tumor.

5:56

Not anymore, you know, within two months,

5:58

the tumor started to explode almost,

6:01

you can see an increase in size.

6:03

There is new areas of enhancement

6:05

within the tumor,

6:06

and that's the time the patient

6:08

underwent subtotal resection.

6:10

The pathology comes back as an anaplastic

6:12

astrocytoma grade three. However,

6:17

this is clearly not behaving like an anaplastic

6:20

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

6:24

this unfortunate child ended up developing

6:29

extensive leptomeningeal metastasis within a year

6:32

and dying from this tumor and

6:34

the metastatic spread. And,

6:36

the reason for that is because these are

6:38

H3 K27 mutant diffuse midline gliomas.

6:43

And actually,

6:44

you can see on the baseline MR spectroscopy

6:47

clearly showing that the tumor is very

6:50

aggressive despite no enhancement,

6:52

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

6:55

low NAA peak suggesting that this is a very

6:59

cellular and proliferating tumor.

7:01

Another example over here in a young patient,

7:04

a 15-year-old presenting with headache and

7:06

vomiting. We have a mass in the right thalamus,

7:11

which is also showing some areas of restricted

7:14

diffusion, some solid enhancement.

7:16

But more importantly,

7:17

this patient actually presented with

7:20

leptomeningeal extensive diffuse leptomeningeal

7:23

spread at the initial onset.

7:24

You can see the diffuse leptomeningeal

7:26

enhancement,

7:27

not just in the brain but also in the spine.

7:30

There is sugar coating of the spinal cord

7:33

and this, this is again, you know,

7:36

another example with H3 K27 mutant diffuse midline

7:41

glioma which will present either

7:44

at initial presentation,

7:45

not that common but eventually will spread with

7:50

leptomeningeal metastasis and usually have poor

7:53

prognosis. And these are different examples.

7:56

Again, you know, children or young adults,

7:59

midline or paramidline masses,

8:02

usually clinically symptomatic poor

8:04

prognosis that's very important.

8:06

And the majority of them will have leptomeningeal

8:09

spread and eventually will have a high mortality

8:14

because of the tumor spread because of the

8:17

leptomeningeal spread. Different examples.

8:19

Another one in the brain stem over here,

8:22

We do see a few cases in the spinal cord,

8:25

as you can see one tumor over here in the spinal

8:28

cord GBM which turned out to be H3 K27 mutant.

8:32

Another one in the Corpus medius, right?

8:34

These are again, same cases,

8:36

you can see younger patients, young adults,

8:38

A spinal cord GBM and A lesion in the cornu medius

8:42

both turned out to be H3 K27 mutant.

8:45

That is one of the reasons, you know,

8:48

because of this marker and the poor prognosis

8:51

associated with this subgroup who came up in 2016

8:56

and classified these tumors actually as a separate

8:59

entity as you can see from this 2016

9:03

WHO classification update.

9:04

And this study clearly shows why these

9:08

tumors should be grouped separately.

9:10

This is a study looking at pediatric GBMs and you

9:14

can see IDH Wild-type GBMs even in pediatric age

9:17

group doing much worse than the IDH mutated

9:20

GBMs as we know from the adult population.

9:22

But look at the K27 mutant

9:24

diffuse midline gliomas,

9:25

they are actually even worse than IDH wild-type.

9:27

Looking at the survival. Now, here,

9:31

here is another example, a patient who had,

9:35

in fact,

9:36

a little older in which is slightly unlike you

9:40

know what we see typically with

9:41

H3K27 mutant midline gliomas,

9:42

at the K27 mutant midline gliomas,

9:46

you have a non-enhancing infiltrative lesion in

9:49

the left thalamus paramidline midline location.

9:53

This tumor was watched because of the innocuous

9:57

appearance and then started to increase in size

10:01

and also high blood volume on the perfusion maps

10:04

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

10:08

the patient undergoes biopsy comes back as H3K27

10:10

mutant diffuse midline glioma undergoes

10:12

standard stoop regimen.

10:19

And this is three months after the stoop regimen,

10:22

the lesion,

10:23

the enhancing part of the lesion starts

10:25

to increase in size. However,

10:28

the blood volume was not very high

10:30

except at the periphery,

10:32

which is slightly lower than the baseline.

10:35

And this was thought to be a pseudoprogression at

10:37

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

10:40

a couple of years later. Now,

10:42

the patient actually is doing relatively well

10:45

with Avastin and standard stoop regimen.

10:48

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

10:51

you know,

10:51

the primary tumor site is still under control.

10:53

The patient has lost a lot of brain volume because

10:57

of the treatment and other things. But you know,

11:00

not all of them,

11:02

some of the diffuse midline gliomas,

11:05

especially if they are BRAF mutant.

11:07

They can do actually a little bit better

11:10

than the garden variety, H3K27 mutant

11:13

diffuse midline gliomas.