Susan Beris, MD, Brain Tumor Symposium

October 21, 2020

October 20, 2020

Presentations by Ranjit Bindra, MD, PhD, Nicholas Blondin, MD, Jennifer Moliterno, MD, FAANS, and Antonio Omuro, MD

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00:17Hi good evening.
00:19Can everyone hear me? Sansa.
00:21Nick blind and can hear me Randy can hear
00:25me alright so two people can hear me.
00:29Thank you to everyone for coming.
00:31I'm Genma, Letourneau, I'm the chief
00:33of neurosurgical oncology at Yale and
00:35we're excited to welcome everyone here.
00:37This is billed as a CME event,
00:40but there's also patients
00:41and providers and families.
00:43Of course that are coming
00:44in addition to providers,
00:46so the more the Marier and we're really
00:49excited for tonight and we look forward
00:52to doing this more in the future as well.
00:55I wanted to start by
00:57acknowledging Susie Barris,
00:59whose name this this CME event holds.
01:02She's a dear patient of
01:04mine as well as Knicks,
01:06who was a pediatrician.
01:08Anne was diagnosed with glioblastoma
01:10two years ago and has done
01:13incredibly and remarkably well an
01:15it's her generosity that allows
01:17us to do these types of events.
01:20So thank you to Susie.
01:22So with that we will start.
01:26What we're going to talk about
01:28tonight is really the state of the
01:30art treatment of primary brain tumors,
01:33and we're going to start with myself
01:35talking about the nurse surgical
01:37approach to brain tumors and then
01:39Doctor Blondin is going to follow me
01:42with the Neural Oncology Perspective.
01:44Doctor Angie Bindra to follow him.
01:46Radiation oncology as well
01:48as other types of research.
01:50I imagine he will also touch upon
01:52and then doctor Antonio Morrow,
01:54who will finish it ouf.
01:56I was talking about clinical trials
01:58and the offerings that we have.
02:00We'll take questions at the end.
02:03Will also take questions after each talk,
02:05seeing how the timing is working out,
02:08and then we'll go from there.
02:10There should be fairly informal
02:11and we hope that you enjoy it.
02:14So let me begin by sharing my screen.
02:37Does everyone see my screen?
02:42Status thumbs up.
02:43OK alright I just seen Nick and
02:45Ranjeet so I'll go based on them.
02:48So if they start to look
02:49bored then I'll just start.
02:51I'll just stop talking
02:52Alright so so again welcome.
02:54I'm going to talk about the neurosurgical
02:56management of primary brain tumors.
02:58As I mentioned, this is our group,
03:00our leadership group for the
03:03brain tumor center and this
03:05was at our most recent retreat
03:07from which was a great event.
03:09One second.
03:14OK. So we are the Premier academic
03:18neural oncology in neurosurgical
03:20oncology program in Connecticut,
03:22and we are fortunate to have the
03:25highest volume of cases of brain
03:27tumor cases and see the most number
03:31of brain tumor patients as such as,
03:34especially as neurosurgeons
03:35were frequently referred.
03:36The more complex neurosurgical oncology
03:39cases by other neurosurgeons across
03:42the region and beyond with this
03:44leads to is the more more key cases.
03:47The types of tumors that are in
03:50more eloquent brain, for instance,
03:52or more functional anatomy
03:53that really interests our care.
03:55And I'm going to focus my talk tonight
03:58on gliomas as well as meningiomas,
04:01just thinking that might be
04:03most interest to the community.
04:05Every tumor that we operate on
04:08undergoes whole exome sequencing
04:09and then we have a multidisciplinary
04:11tumor board where all of us sit.
04:14I lead it as well as a precision brain
04:16tumor board where we really personalize
04:18the care for each and every patient.
04:24This was some data that I had presented
04:26about our brain tumor center and
04:29specifically about the neurosurgery
04:31neurosurgical oncology aspect of it.
04:32This was pulled from 2017, so actually
04:35has increased quite a bit since then,
04:37but I wanted to be honest with the numbers,
04:41so we have about half the share
04:43of neurosurgical oncology
04:44discharges throughout the state.
04:46I am fortunate to be the busiest
04:48brain tumor surgeon, but the other
04:50two busiest brain tumor surgeons are.
04:53In our center as well, and we run
04:56domestic and international programs.
04:58This is a typical practice for
05:01us in our surgical oncology,
05:03and so you can see here,
05:06glioblastoma involving the Motor Strip,
05:08large CP angle tumors such as epidermoid's.
05:12Here are some atypical meningiomas
05:14as well as intra ventricular tumors.
05:17And again, these are just some more
05:20cases that we frequently see again,
05:22meningiomas CP angle tumors,
05:24large acoustic neuromas,
05:25intra ventricular tumors,
05:26epidermoid tumors that have been re
05:29operated typically in the past as well.
05:31So our mission,
05:32which is likely similar to all the
05:35other providers that are on here,
05:37is to improve our patients quantity
05:40and quality of life and the way that
05:43we try to do that is to provide the
05:46most excellent patient care possible.
05:48We have advanced techniques and
05:50expertise as well as the resources
05:52and the infrastructure to do that.
05:55Again, as I mentioned,
05:56we have a multidisciplinary
05:58treatment program and we're always
06:00happy and willing to provide that
06:02with the community as well.
06:04And then we offer our patients support,
06:06realizing what a difficult
06:08diagnosis of brain tumor can be.
06:11So the goals of primary brain tumor surgery.
06:13Of course,
06:14one is to establish the diagnosis
06:15to guide further treatment,
06:17recognizing that surgery
06:18alone is not the answer.
06:20In most tumors, and really we,
06:23we aim to Resect as much
06:25tumor as safely as possible.
06:27There's some exceptions to this,
06:29of course.
06:30They're very few.
06:31This not only helps the patients
06:33from a symptomatic standpoint,
06:35but really has shown across the board to
06:37have overall and progression free survival
06:40benefits in various types of tumors.
06:42Old tumors, for the most part,
06:45especially gliomas in meningiomas
06:47which will talk about tonight.
06:49And,
06:49of course,
06:50that issue that we obtain from from
06:53the surgeries can help guide more
06:56personalized treatment as well.
06:58So what I like to say is,
07:00is we have ways to make what
07:02others deem as inoperable,
07:04tumors operable,
07:05and so there are some reasons and
07:07tricks that allow us to do that.
07:09So for one we have sub specialized expertise,
07:12and so Veronica Chang and Joe Pete
07:14Meyer on there in that picture with me.
07:17All we do is brain tumor surgery
07:19in our brain tumor surgeons.
07:21All they do is brain tumor surgery.
07:23And in fact we're even further
07:25subspecialized into primary brain
07:26tumors and metastatic brain tumors etc.
07:28And so.
07:29There really is something to be said
07:31for neurosurgeons to do the same
07:34type of subspecialty surgery day
07:36in and day out.
07:37We similarly have advanced imaging
07:39capabilities, so Rob Fulbright,
07:40for instance, are one of our amazing
07:43new radiologist as well as others.
07:45Allow us to understand the function
07:47of the brain and so functional MRI's
07:50and other more sophisticated imaging
07:53techniques that guide us in surgery.
07:55We use GPS system which is standard
07:57on all of our cases and then also
08:00in addition to that I typically
08:03use the ultrasound in every case.
08:06Not sure if my mouse is.
08:08Coming up probably.
08:09Ranjeet says yes but that big white
08:12thing in the middle is the brain
08:14tumor and then the little black thing
08:17in the middle is the carotid artery.
08:20So understanding the relationship
08:21between the two is of course important
08:24but also allows me to know how
08:26much tumor I have removed during
08:28the surgery and so I can always go
08:31back and remove more if it's safe.
08:33The gold standard to really maximizing
08:35the extent of resection is the Inter
08:38operative MRI and so we're the only
08:40center in the state of Connecticut.
08:42It has a three Tesla MRI or any MRI
08:45actually in our operating room,
08:46which you can see we're standing in
08:48front of and I'll show you an example
08:50of that later and it really does make
08:52a difference in terms of the outcomes
08:54and how much were able to remove.
08:57Going back to our sub specialized expertise
08:59were able to perform functional mapping
09:01and more sophisticated microsurgery
09:03which relies on neurophysiology.
09:05It's standard on nearly all of our cases,
09:08an really the gold standard to
09:10that also is awake craniotomy that
09:13allows us to operate in functional
09:15parts of the brain that others
09:18would would deem inoperable in.
09:20Just rely on a biopsy rather
09:22than try to maximize reception.
09:28This was a slide that was given to me by
09:31the chair of MGH, which I really like.
09:34It shows that the more specialized the
09:36surgeon is in cranial surgery and brain
09:38surgery, the better the patients do,
09:40and I think that's even more
09:42true for brain tumor surgery,
09:44meaning that to have specialists
09:46who only do brain tumor surgery,
09:48that outcomes are that much better.
09:50And that's again what we're
09:51what we're most interested in.
09:53And then, of course,
09:54recognizing that it doesn't end with surgery.
09:57And relying on our colleagues in neurology,
10:00radiation?
10:00Oncology and then novel therapies as
10:03well to really push the field forward.
10:06So I wanted to use a few case illustrations
10:09just to showcase what we're able to
10:12do and also drive home the point of
10:15how important the maximization of
10:18extent of resection is maximizing.
10:20So this is a patient actually that
10:23Doctor Blondin referred to me and we
10:26see things like this all too common
10:29in our practice, unfortunately.
10:30So this was a patient who presented
10:33with a phasia and you can see at the
10:36outside hospital. This was his scan.
10:39In December 2018,
10:40he underwent craniotomy for tumor.
10:41This is his post op CIT.
10:44And then this is his post op MRI
10:46done in January and you don't have
10:49to be a brain surgeon to see that
10:52the tumor that's here,
10:53which is a glioblastoma which is in
10:56the left side of his brain which is
10:59near the language is very similar
11:01in appearance to before surgery.
11:03And again we see this, unfortunately because.
11:08Other people don't have the
11:10capabilities that that we might,
11:12so he was kindly referred to me.
11:14We ended up getting that functional
11:16MRI image Ng that I had mentioned,
11:19which allows us to understand the
11:21important function of the brain and
11:24I ended up keeping him awake during
11:26surgery and was able to remove all of
11:28it and he was able to go on and and be
11:31treated with ajibon therapy and his
11:34aphasia improved even more importantly.
11:36So again being able to do.
11:39These types of things awake,
11:41craniotomy and other more sophisticated
11:43surgery can really help patients.
11:47This is just a slide about are
11:50awake craniotomy protocol and so
11:52some patients get nervous about
11:53the idea of awake craniotomy.
11:56And actually, it's one of the safest
11:59procedures that we perform an incredibly
12:01well tolerated and I have a video to
12:05share about that we rely on our great
12:08collaboration with Neural Anesthesia
12:10and so that's doctor Shilpa Rao.
12:12She's at neuro anesthesiologist who really
12:15make sure that the patient is comfortable.
12:18And can tolerate being awake.
12:19And we reserve this when we're
12:22operating in areas such as these with
12:24tumors that are near the language
12:26area or even near the motor area.
12:28And again,
12:29this allows us to maintain patients function.
12:32So the following is about a
12:34four minute video or so.
12:35I hope you don't mind,
12:37but I think it it really showcases
12:40nicely in terms of these procedures.
12:43To
12:44a Fox 61 exclusive material
12:45scenario when undergoing surgery.
12:46Waking up in the middle of the
12:48procedure and knowing what's going on.
12:50But in some cases that can be a
12:52life saver like savor an necessary.
12:54We're going to explain that in a moment.
12:56But first we do want to introduce you
12:59to a man named Andy Andy is a husband
13:02and father of two kids and a nurse.
13:04Another interesting fact about him,
13:05he's also a professionally trained singer.
13:07He's even performed with his
13:08church choir at Carnegie Hall,
13:10but Andy felt his entire life come to a halt.
13:13When he was diagnosed with brain cancer,
13:15he needed surgery to remove as
13:17much of a tumor as possible.
13:19That tumor in the part of his
13:21brain that controls speech.
13:22And, yes, singing.
13:23That's where a special surgery comes in.
13:26Surgeons at Yale,
13:27New Haven Smilow Cancer Hospital
13:28have perfected a procedure called
13:30an awake craniotomy.
13:31They invited us into the operating
13:33room and we did not hesitate to see
13:35this incredible procedure first hand.
13:41In an operating room at Yale,
13:43New Haven Hospital.
13:45Doctors are working to remove
13:47a tumor from the brain of a
13:5031 year old man named Andy.
13:52He is a singer, yeah,
13:53a husband and father of two or
13:56most surgeries waking up in the
13:58middle of the operation would
14:00be a disaster. So he is asleep
14:04during the initial approach.
14:07Sure, Andy and then
14:08we wake him up.
14:11Any Sacile surgeons have
14:12drilled through his skull and have already
14:15begun to remove part of a tumor located
14:18on the left side of his temporal lobe.
14:21The area which controls language.
14:24Medical staff puts a microphone on him.
14:27It's not for our cameras,
14:29it's so the entire room,
14:30including the operating surgeon,
14:32can hear what Andy has to say.
14:36She won, the procedure is
14:38called an awake craniotomy.
14:39You have a headache.
14:40I was telling you earlier I I
14:43don't know if it's from the brain
14:45surgery or the fact that I haven't
14:47had a Cup of coffee this morning.
14:50Nuro physiologist,
14:50Brooke Callahan sits next
14:52to him and begins her work.
14:54I am going to say it's sentence and
14:56I want you to repeat it after me.
14:59The seashore smells like salt.
15:01The seashore smells like salt.
15:02Their interaction can be heard
15:04on a speaker throughout the room.
15:06Neurosurgeon Doctor Jennifer
15:08Moliterno has mastered multi
15:12tasking operating and listening.
15:13Yeah,
15:13he's doing great Doctor Moliterno
15:15and her team work diligently
15:17to remove as much of the tumor
15:19as possible. What she can't see are critical
15:22microscopic language fibers
15:23which are splayed over the tumor.
15:25The best way to try to remove
15:27as much tumor and preserve his
15:30language is to do it with him.
15:32Oh it get too close to those
15:34critical fibers. You'll know it.
15:36What do you do in a chair?
15:41So here he loses his speech.
15:45Yeah, little bit of confusion, so
15:47that's a great way to me to tell me to stop.
15:50And so even though there might
15:52be a little bit of tumor there,
15:54the risk and benefit of removing
15:56that tumor and having him not speak
15:59for the rest of his life tells you
16:01exactly what the right decision is.
16:03If he was asleep, I would have had no idea.
16:06As Doctor Moliterno
16:07continues operating in a
16:08safer spot, and he surprises
16:10us when this happens.
16:17He does in the middle of surgery.
16:20Andy, a classically trained singer,
16:22shares his talent. Again.
16:282 1/2 hours into the procedure,
16:29doctor Moliterno decides
16:30it's time to wrap up.
16:31The surgeons are done with the
16:33first part of the surgery.
16:35So what's happening now is they're
16:36bringing in an MRI machine and
16:38they're going to look at the work
16:40that they did and see how much of
16:42the tumor they were able to remove.
16:46We go into another room and are
16:49able to sit with Doctor Moliterno
16:51as she analyzes her work.
16:53The before here is the tumor and after.
16:59You don't have to go back
17:01in and feel satisfied.
17:03Him being awake allowed us to get that
17:06outcome and preserve his function.
17:08Now Andy was back home with his
17:10family two days after surgery,
17:12five days after the surgery,
17:14he was able to sing at his son's baptism.
17:17He's also saying again with his
17:19church choir and the Yale Camarada,
17:21which is a professional choir,
17:22just a couple of weeks ago and he is
17:25undergoing chemotherapy and radiation.
17:27But he does say he's feeling good
17:29and of course, warm wishes to him.
17:31He is just a great guy
17:33and so that is exactly the
17:35reason we do what we do.
17:40This is another example of how we don't
17:43necessarily need to keep patients awake,
17:46but they do benefit from being
17:48more aggressive with surgery,
17:49so this was a patient back in 2013 who
17:53underwent a biopsy because it was felt that
17:57the tumor that's here deep within the brain.
18:01Was too dangerous to remove,
18:03so he underwent a biopsy.
18:04Came back as a glioblastoma he was referred
18:07then to me by the Oncologist in the area,
18:10and I felt that I could remove it safely.
18:14And so I ended up doing an enterprise.
18:16All socal approach and remove the tumor.
18:19Here's a good example of how even for
18:21a brain tumor surgeon such as myself,
18:24this is our intra operative MRI.
18:26This is the intra operative scan and you
18:29can see I left a little bit of tumor there.
18:33And so that's the benefit of
18:35having that Inter operative MRI,
18:37because sometimes a little bit
18:39of tumor gets tucked underneath
18:41the brain and you can miss it.
18:43Even I can miss it.
18:45So I went back and ended up getting
18:47a nice gross total resection on
18:50him in that same setting with that
18:53MRI of course it came back as
18:55glioblastoma with a poor profile an
18:58he remained neurologically intact.
18:59He went on to undergo stupid
19:01standard treatment with Joachim
19:03bearing as his neuron cologist.
19:05He enrolled on a clinical
19:06trial of doctor binge.
19:08Chris and then switch to another
19:10clinical trial over the years and
19:13then ultimately was continued on
19:15bevacizumab and progressed about 3 1/2
19:18years following his initial surgery,
19:20and I'm sure in she will talk
19:23more about his trials.
19:26This was his recurrence here,
19:27so he was referred back to me.
19:30This is 2017 for the initial surgery
19:32was 2013 referred back to me.
19:34I ended up doing a much wider resection
19:36of his tumor this time and this is
19:39exactly what our path reports look
19:41like in the sense that not only
19:43do we know that it's a GB M and
19:46have some of the molecular makeup,
19:48but with the whole exome sequencing
19:50were able to really understand the
19:52genetic the genomic makeup and so here
19:55what we found was that his tumor had
19:57become a hyper mutated tumor phenotype.
19:59These tumors we know.
20:00Are incredibly responsive to immune
20:02mediated checkpoint inhibitors.
20:04He was started on Nivola map as a result.
20:08He continued for the next couple of
20:11years or so on nivo and then switch to
20:15Avastin and then actually both back and
20:18forth an in 2018 he had some recurrences,
20:21Avastin, which stopped and I respected him
20:24again and so seven years nearly seven years.
20:28This December he will be out from his initial
20:32glioblastoma surgery and so as I always say,
20:35it's not that all of our
20:37patients will survive.
20:39Seven years with glioblastoma.
20:40I wish that was certainly the case,
20:43but it is definitely the case in
20:45his an I think that it was really
20:47being aggressive with surgery,
20:49having novel Therapeutics which
20:51we have and then also just
20:53continuing added in an understanding
20:55the genomics of the tumor that allowed
20:57us to really tackle his tumor so well.
21:00I do know for a fact if he
21:02had stopped at the biopsy,
21:04he certainly would not be alive now
21:06and so that's where aggressive surgery.
21:09Really matters, I just want to
21:11switch gears quickly to meningiomas
21:13because I think this is something
21:15important to talk about,
21:16especially for community providers.
21:18What we're understanding more
21:20and more is that these tumors are
21:22not as benign as once thought,
21:24and understanding the tumor
21:26biology is really important,
21:27and that's something that
21:28we try to do here at Yale.
21:31This is a patient who was referred to me
21:34who initially had surgery in 2015 or 14.
21:37I can't see on my slide.
21:40And underwent surgery at another
21:42hospital in Connecticut.
21:44This is his recurrence in 2017.
21:46At that point he had went to New York City,
21:51underwent radiosurgery and
21:52unfortunately was complicated by
21:53a lot of medical problems related.
21:56He had intractable seizures and weakness.
21:59He continued to have growth,
22:01as you can see between 2017 and 2019,
22:042019,
22:05he was referred to me when he was
22:08in a wheelchair.
22:10With intractable seizures,
22:11so the question is,
22:13is whether or not we could have
22:15predicted this better the first
22:17time around and you can see here he
22:19underwent a gross total resection,
22:21but again,
22:22could this have been handled differently?
22:24Initially this is a similar case
22:26of a patient who underwent.
22:28I don't have his initial scan,
22:30but had a small meningioma that was
22:33in this area was also told similar
22:35to the initial patient that was it
22:38was a benign meningioma and he was.
22:40Lost to follow up,
22:42he returns in 2016 with visual problems.
22:46His neurosurgeon then sent him to me.
22:50And we performed a gross total
22:52resection of his tumor with the
22:54help of my kelp revich from plastics
22:56and reconstructive surgery,
22:58as well as Ben Judson and reconstructed.
23:00This is just some muscle to form
23:03a flap and steal it off,
23:05but could this have been managed
23:07differently the first time?
23:09And why are these benign meningiomas
23:11behaving this way?
23:12And so the last 10 years or so we as
23:14well as others have really understood
23:17or begun begun to understand the
23:19genetic Genomic landscape of.
23:21Meningiomas and we know that there's
23:24specific genomic subgroups that
23:25underlie grade one meningiomas,
23:27and these are the driver mutations that
23:30cause these tumors to happen to occur.
23:33Rather,
23:34we also have a unveiled pathways to
23:37aggressive meningioma in the lab for
23:39part of it, but also clinically,
23:42as we have here,
23:43and so we use this information in
23:46real time in a paper that just came
23:49out this past week in Neurooncology.
23:52We looked at at our experience with
23:55meningiomas and basically found
23:57that molecular subgroups itself,
23:59the driving mutation that's
24:00causing these tumors to form,
24:03that these subgroups have divergent
24:05clinical courses at two years of follow-up,
24:08and so there's aggressive types
24:10of grade one tumors versus
24:12more benign types of grade one tumors.
24:15So all grade one meningiomas
24:17are not created equally,
24:19and that's basically what we've shown here.
24:23This was really the first
24:24of that study to do that.
24:26What we also have found and published
24:29previously is that these subgroups localize
24:31as you can see along the skull base.
24:33And again I can go into this in
24:36further detail at another time,
24:38but just the take home point
24:40is that not all benign,
24:41not all grade one meningioma's
24:43behave behind benign,
24:44so it's very important to
24:46be aggressive with them,
24:47and so this first case example that
24:49I gave turned out was not benign.
24:52This was an atypical meningioma.
24:53This was the pathology report
24:55that we received.
24:56As well as the whole exome sequencing
24:59information and what this told us
25:01based on what we know was that this
25:04was initially a grade two tumor
25:06when he was initially diagnosed,
25:07but unfortunately was not diagnosed properly,
25:10and so again goes back to the benefits of
25:12having a center that does this routinely.
25:15A center that has experts that are
25:17really dedicated to understanding
25:19this at a much deeper level and
25:21that's what leads us to our precision
25:24brain tumor treatment program,
25:25which I discussed in my colleagues,
25:27will also discuss.
25:29We have all of our patients
25:31navigate through our program,
25:33knowing that multidisciplinary programs
25:34can be tricky and overwhelming,
25:36and so we try to organize that
25:38as best as possible.
25:40We offer a brain tumor support
25:42group which meets monthly.
25:44We have an acoustic neuroma support
25:46group that meets quarterly and then
25:48of course we have funding for our
25:51patients and so Connecticut Brain Tumor
25:53Alliance we've partnered with for years,
25:56which has been incredibly
25:57helpful for patient support.
25:59As well As for research and
26:01the Lovemark Foundation,
26:02more recently has donated
26:04$350,000 to us so far,
26:06with every cent going to our patients
26:08to help them get through treatment.
26:11So, in summary,
26:12from a surgical perspective,
26:14it's important to be as aggressive
26:16and as safe as possible.
26:18It makes a big difference
26:20in terms of outcomes from a
26:22quality and quantity standpoint,
26:24and we're certainly able
26:26to do that here at Yale,
26:28we try to work as collaboratively
26:30as possible with the community.
26:32Knowing in the end we just want
26:34our patients to have the best care
26:36possible and be as close to home
26:38as possible and then feel free to
26:40reach us anytime there's our number.
26:43And there's my email.
26:44Thank you.
26:52So next, it's my pleasure to introduce
26:55doctor Nick Blonde and he is one of
26:59our wonderful neural oncologists,
27:00an assistant professor.
27:05Excitable turn off.
27:07Can you see my screen?
27:09Let's see the.
27:11Thumbs up excellent.
27:13Thanks again for the opportunity
27:14to present here will be providing
27:17some neurooncology updates and
27:18brain tumor management.
27:20For disclosure on the Yale principle
27:22investigator from a trial sponsored
27:24by the nonprofit Global Coalition
27:26for adaptive research or Qi Car
27:28and I also have done consulting
27:30and speaking for novocure,
27:32the company that produces the optune device.
27:34I produce this into presentation itself,
27:37so I'll be providing updates
27:39on glioblastomas and then a
27:41few slides on meningiomas.
27:43As you know,
27:44glioblastoma is the most common
27:46malignant primary brain tumor in adults,
27:48and it arises from the malignant
27:50transformation of glial cells,
27:51which are the normal supporting
27:53cells of the brain.
27:54The tumor is composed of modules
27:56comprising the bulky tumor as well
27:58as infiltrative glioma cells that
28:00diffused through the brain tissue.
28:01And because of this,
28:03infiltrated nature of the disease,
28:04the tumor, unfortunately,
28:05cannot be cured by surgery.
28:07However,
28:07the extensive surgery does affect
28:09the prognosis and patients
28:11that can have a more extensive
28:12surgery or gross total resection.
28:14To live longer.
28:15And then following maximal
28:17safe surgical resection,
28:18patients will require further
28:19treatment or else regrowth will occur,
28:22typically starting within two to three
28:24months after the initial surgery,
28:25and these follow-up treatments
28:27comprise radiation and chemotherapy.
28:31Glioblastoma is typically discovered
28:32in an adult that has a first time,
28:35unprovoked seizure.
28:36Other symptoms which can arise
28:37leading to the discovery of a
28:40glioblastoma can include progressively
28:41worsening headaches, visual changes,
28:43the outset of focal weakness,
28:45or sensory and pyramid,
28:46or cognitive impairments such as
28:48change in personality or memory.
28:50Typically, these neurological symptoms
28:51will lead someone to see their primary
28:54care doctor or neurologist or seek
28:56treatment in ER where imaging is done
28:58demonstrating a Mass in the brain.
29:00Then we obtain an MRI of the brain
29:02which typically has characteristic
29:04features of glioblastoma.
29:06They appear as mass lesions within the brain.
29:09Typically causing swelling around
29:10that region and compression
29:11on other print structures,
29:13and we usually can have a suspicion
29:16based on the MRI that this tumor
29:18is in fact a glioblastoma.
29:20However, we need surgery,
29:22surgical intervention or at a biopsy.
29:24At minimum,
29:25tap tissue to determine that the
29:28tumor is in fact a glioblastoma RGB.
29:31In terms of prognosis for glioblastoma,
29:34there's a few factors which impact prognosis.
29:39Critical one really is age,
29:41age of the patient.
29:43So particularly for patients
29:45age 70 and older,
29:47they may have more complications
29:49that arise from treatments including
29:51radiation and chemotherapy,
29:52and so different treatment considerations
29:55or deescalating therapy may actually be
29:57preferred for this patient population,
29:59the extent.
30:00Surgical resection also has
30:02an impact on prognosis.
30:03As I mentioned,
30:04and then the performance status of
30:07the patient following their surgery
30:09also impact prognosis and show us
30:11picture here on the side of the slide
30:14for the Karnofsky performance status
30:16of seeing how a patient is and the
30:19hope is that following their surgery,
30:21the patient will have a full
30:23recovery and get back to 100% normal
30:26functioning and ability to work.
30:28Typically patients will have a good recovery,
30:30a karnofsky.
30:31Scale of 80 to 90 is like a good goal,
30:34even to shoot for for initial recovery
30:36from surgery and the performance
30:38status really just depends on where the
30:40tumor was located in the brain and the
30:42size of the tumor which it was discovered.
30:45And then more recently discovered
30:47that there is some molecular subtypes
30:49of glioblastoma that also have a
30:51very significant implication for prognosis.
30:532 main factors being the
30:55MGMT status and I DH,
30:57one status and more recently discovered.
30:59Other mutations are also important
31:02to help prognosis patient.
31:04In terms of the standard of care therapies
31:07for glioblastoma after the patient
31:09undergoes maximal safe surgical resection,
31:11they received radiation therapy,
31:13along with Tim's olamide
31:14chemotherapy or TM ZTMZ's pills,
31:16which is taken at home.
31:18It's A kind of chemotherapy
31:20that damages DNA in the cell,
31:23called an alkylating chemotherapy,
31:24and is given with radiation and then
31:27subsequently had monthly cycles by
31:29combining Timbers Olamide chemotherapy with
31:31radiation in a clinical trial population.
31:33The average survival time was improved
31:35from 12 months to 14.6 months.
31:37Antennas olumide has been the standard
31:40of care for treatment since 2005.
31:42A second line,
31:43chemotherapy,
31:44which is also commonly used asbestos,
31:46is a mav, also referred to as a vast in Orem.
31:50Basi and bevacizumab is a biological drug
31:53which binds a hormone called veg F that
31:56is responsible for brain swelling and
31:58growth of blood vessels into the tumor.
32:00By administering bevacizumab,
32:02patients have improvement of brain swelling
32:04as sometimes experience shrinkage of
32:06tumor or stability at in a clinical trial.
32:09Addition of bevacizumab having
32:10increased average survival time
32:12patients out to 16 months.
32:14Some patients going longer and it
32:16didn't matter if patients receive that.
32:17This is a map up front for treatment
32:20along with radiation to Missoula might,
32:22or if they received it at recurrence,
32:24so it's typically saved
32:26for use in recurrence.
32:27Finally,
32:28the optune device has been approved
32:30for treatment of newly diagnosed GBM
32:32following completion of radiation
32:34therapy options are portable medical
32:36device that delivers an electrical
32:38field that inhibits the mitosis of
32:40tumor cells functions as an anti
32:43mitotic therapy and is intended to be
32:45used along with mazola might cycles
32:48in the clinical trial population.
32:50Patients that were willing and able
32:52to use optune the use of optune
32:55increased the average survival time
32:57from 19.8 months to 24.7 months.
33:00So these are the three standard
33:02therapies which typically offered to
33:04essentially all of my patients for
33:07treatment consideration, and you see,
33:09we have improved average survival time
33:11by about doubling over the last 15 years,
33:14but there's certainly more to go.
33:17Additional chemotherapies could
33:18be considered for select patients,
33:20and these include Lomustine,
33:21the PCV, chemo, combination therapy,
33:23regehr, Afan, if,
33:25or other targeted therapies,
33:26and these are in the NCCN guidelines.
33:30And so I touched on molecular features
33:32being important for prognosis.
33:34It was discovered about 10 to 15
33:36years ago that The MGM T status
33:39is important for prognosis.
33:40Patient MGMT is an enzyme that can
33:43repair the damage done to DNA from
33:4510 mazzola might chemotherapy and the
33:47gene is controlled by a promoter which
33:50is turned on and off by methylation status.
33:52Metallated tumors have turned off
33:54the promoter and so the enzyme is
33:57in low levels in those tumors.
33:59Thus, patients with methylated GB M.
34:01Help more sustained damage from Tim's Ola,
34:03my chemo and those pieces will live longer,
34:05so I'm GMT.
34:06Metalation status is important
34:07to figure out for patients,
34:09and we assessed us on all of our patients.
34:12Secondly,
34:12the ID H1 status is also important
34:15to determine.
34:15This is a gene involved with
34:17tumor metabolism and is typically
34:19mutated in astrocytomas,
34:20a less aggressive kind of brain cancer.
34:23If Glioblastomas discovered with ID H1,
34:25that indicates that in fact it was
34:27an astrocytoma originally which has
34:29become more aggressive but still may
34:31have a better prognosis compared to a tumor,
34:34which has a normal ID HG that's
34:36referred to as wild type.
34:39And then recently other mutations
34:41have been discovered that have
34:43targeted therapy options.
34:44These include the beer at V.
34:47600 E mutation,
34:48NTRK Fusion,
34:49both which have FDA approved therapies,
34:51an FG FR3 Fusion is under development,
34:54currently with a few drugs
34:56being devised for treatment.
34:58Also mismatch repair deficiency.
35:01If that's discovered in the tumor
35:03Pember Lizum app or keytruda
35:05can be used as FDA indicated
35:07for treatment in those tumors,
35:09and I have your picture
35:11of both Water Foundation.
35:12One report would look like up at the top,
35:15showing those genomic alterations
35:17identified and our own in-house system.
35:19Our whole exome sequencing is
35:20doctor maternal referenced.
35:21The benefits of the whole exome
35:23sequencing is that beyond just looking
35:25at the Genomic alterations identified,
35:27we learn about copy number alterations
35:30and copy number alterations occur
35:32from gain or loss of chromosomes.
35:34And we know now we have lost,
35:36always comprised of many
35:38chromosomal abnormalities,
35:38gains and losses of chromosomes
35:40or chromosome fragments,
35:42and that contributes to
35:43their malignant behavior.
35:46Then amino therapy has made
35:48many gains in cancer treatment
35:50over the last several years.
35:52It's still in development for glioblastoma.
35:54As I mentioned, Keytruda is approved,
35:57but only in tumors,
35:58exhibiting DNA mismatch repair,
36:00which is a very small percentage of GM.
36:03A few studies have been
36:05done in the Checkmate 140.
36:07Three study of recurrent GBM treatment
36:09patients received either new volume
36:11AB Devo versus Bevis ISM at a vast.
36:14In an average survival time was
36:16equivalent in the clinical trial
36:17population approximately 10 months.
36:19Newly diagnosed tossed patients
36:21were also studied with Napoleon
36:22map with results forthcoming,
36:24but there doesn't seem to be a
36:26big impact overall for those study
36:29populations and then recently a study
36:31was looking at Pember Lizum app or
36:34keytruda treatment in patients with
36:36recurrent GBM that could receive
36:38surgery and impatience that entered the
36:40study and received Pember Lizum app
36:42along with surgery for recurrent G BM.
36:44Their average survival was 417 days versus
36:47228 days in patients that received.
36:49Keytruda alone,
36:50so this is in further development.
36:52We have a trial coming up at Yale which
36:55I believe Doctor Omuro will be talking
36:57about later in this talk about the strategy.
37:01And then for our patients critical
37:03factors of glioblastoma treatment
37:05are cortical steroid management
37:07and anti convulsant management.
37:08So cortical steroids like dexamethasone can
37:11be extremely helpful to treat brain swelling,
37:14make patients feel better,
37:16reduce neurological
37:17disabilities in the short term,
37:19but with long term steroid use.
37:21A number of adverse effects can happen
37:24due to hormonal changes in the body.
37:27Patients can develop diabetes fractures,
37:29bone weakness.
37:30And lethargy condition called
37:32adrenal insufficiency.
37:33So managing corticosteroids
37:34closely is important.
37:35Something I look at with every patient,
37:37every visit,
37:38every time.
37:38What dose of dexamethasone early
37:40on it cannot get them off and the
37:43usage of bevacizumab as a steroid
37:45sparing agent has come into the floor
37:47and neurooncology is quite helpful
37:49drug to get people off of steroids
37:52if they've been on for too long.
37:54And other features that we have
37:56in our brain tumor center that are
37:58critical for patients or counseling
38:00and social work.
38:01As doctor maternal mentioned,
38:03we hook up the patients with our
38:05navigator and work with them.
38:07Figure out disability for them and
38:09how to move forward with their life.
38:11After this is devastating diagnosis
38:13and I think about for patients,
38:15physical therapy rehab exercise
38:16in the role of nutrition.
38:21Alright, now let's just
38:23briefly talk on meningiomas.
38:25As doctor maternal mentioned,
38:26meningiomas are typically
38:27thought of as benign tumors,
38:29but they may not be booked benign
38:31in nature or they can cause pretty
38:34significant neurological disabilities.
38:35For patients.
38:36These tumors arise from the neoplastic
38:38transformation of arachnoid cap cells and
38:40typically are identified as a solid nodule,
38:43which may be calcified.
38:44There's three grades historically have
38:46meningiomas Grade 1, two, and three,
38:48but as doctor maternal mentioned,
38:50we now know that based on the
38:52genomics of these tumors,
38:54tumors that appear to be grade one.
38:57Mythology may actually act
38:58in a more malignant fashion,
39:00like a grade two tumor or
39:02even more significant.
39:04So I drew some arrows here.
39:06the Red Arrows pointing
39:07at a small meningioma,
39:09the Blue arrows pointing
39:10at a large meningioma.
39:12Small and asymptomatic meningiomas may
39:14not need treatment beyond observation,
39:16but large meningioma is
39:17typically caused symptoms.
39:18Those are symptomatic meningiomas,
39:20and those require treatment.
39:21Neurosurgical intervention being the
39:23primary treatment modality and then
39:25radiation therapy being the 2nd.
39:27Treatment modality.
39:30So if patients have exhausted
39:32surgical and radiation treatment
39:33modalities but still are in good
39:36enough condition to undergo some kind
39:38of further tumor directed therapy,
39:40medical therapies could be
39:41considered for treatment.
39:42We can look at their genomic
39:44analysis and see if in fact there
39:47may be a targetable mutation,
39:49such as the small mutation which
39:51hedgehog pathway drugs may have
39:53some effect in that's being studied,
39:56and then recently a paper was
39:58published looking at a combination of.
40:00Everolimus in octreotide so is the
40:03phase two servorum study and in
40:05this study approximately half the
40:07patients had progression free survival
40:09after a year which is better than
40:12historical trends for this patient
40:14population and Pembrolizumab also
40:16exists again for tumors that may
40:18have mismatch repair deficiency and.
40:20I manage patients with newer
40:23anticonvulsant drugs such as Lacosamide,
40:25Verace,
40:25Tam and others,
40:26and these drugs have less
40:28side effects than the older
40:31anticonvulsants like Deppe Code or
40:33finito and better seizure control.
40:36Alright,
40:36I think at that point conclude my
40:39talk and pass the Doctor Bindra in
40:42our radiation oncology division.
40:53OK, can you folks hear me?
40:57Wonderful OK, well thanks so much.
40:58A wonderful series of talks and I'm
41:01going to tell you a little bit today.
41:03An update on some of what we're doing
41:06in radiation oncology as it relates
41:08to primary brain tumors and recognize
41:10that we have a diverse audience of
41:12Physicians as well as patients as well.
41:15And so thank you so much for coming here.
41:18My disclosures will not be talking
41:20about any of these companies
41:21that I've recently started,
41:22but really just dive dive right into it
41:25so we'll start with some advantages and
41:27new approaches in radiation therapy.
41:29It's Milo.
41:30Then move on and tell you a little bit
41:32about Proton Therapy and it's hopefully
41:34soon to be arriving planning on the horizon,
41:37and then we'll end with a little bit of
41:40work that I also do in the laboratory.
41:42I spent about half my time running
41:45at a Glioma lab trying to translate
41:48work into the clinic.
41:50So a few interesting technologies
41:52that have been really progressing
41:53and developing quite nicely at Yale.
41:55We are very actively using something
41:58called the novelis exact track
41:59system for CNS tumors,
42:01and this is just a a schematic of the
42:04instrument showing the patient here.
42:06This is a 6 degree couch,
42:08which means that 6 degrees of
42:10freedom can move side to side,
42:12front to back and then can actually tilt and
42:15actually has imaging sources that come out.
42:18We call orthogonal angles at.
42:19And they can.
42:21They can be repeated to get very,
42:23very close,
42:24accurate delineation of the
42:26treatment area during treatment.
42:28And this is sort of just a little
42:30snapshot of the images that we get
42:33from those orthogonal cavey images.
42:36And we actually have automated
42:38alignment algorithms,
42:39so we can actually get down to about
42:41.3 millimeters of accuracy within a
42:44framless system using the novelis platform.
42:47Yeah,
42:47we're able to treat a very wide range of.
42:51Primary CNS tumors,
42:52as well as metastases,
42:54and these are just some heat map
42:56showing incredible of focused delivery.
42:58Sparing areas like the spinal
43:00cord and then shown here.
43:02Critical areas like the brainstem.
43:06Are in parallel.
43:07We also have a very active gamma knife
43:09radiosurgery program and a doctor moliterno,
43:11and the team here are
43:13involved with this as well,
43:15but this program is led by
43:17doctor Chang and doctor you,
43:18and it's really a fabulous program,
43:20and it's great to see it evolve over
43:23the last 20 years I was actually a
43:26medical student here in the early 2000s,
43:28and I've seen this program grow.
43:30For those of you that don't
43:32know the gamma knife,
43:33essentially about 200 sources of pencil beam.
43:36Radiation there are focused
43:37right on the tumor,
43:39and by doing that we can achieve a very,
43:42very significant steep dose.
43:43Dropoffs shown here,
43:44and we can treat tumors that are 1
43:46millimeter if not and or areas that are
43:491 millimeter or smaller in patients,
43:51and this is typically using
43:53a frame that we have
43:55fixed to the patient.
43:56But you'll notice in this picture we
43:58have a new instrument called the icon,
44:01and that's actually shown here.
44:03This is just set up over the last two years.
44:06And this is really state of the
44:08art radiosurgery at Yale and using
44:10this technology were actually
44:12able to treat patients without
44:14a surgical placement of a frame.
44:16So these patients can lie in the table,
44:19have a mass placed on them,
44:21and have a little bit more freedom
44:23to move while still maintaining
44:24a very accurate treatment.
44:26So what sort of treatments do we do?
44:29We do with these technologies,
44:31so we can really treat all sorts
44:33of primary and brain metastases
44:35with this approach.
44:36We do treat Glioma both newly
44:38diagnosed in recurrence with these
44:39technologies and modalities.
44:41Meningiomas as we just heard
44:43about acoustic schwannomas,
44:44we also treat pediatric brain tumors,
44:46especially when we're very concerned
44:48about dose exposures in critical
44:50areas as well as re radiation,
44:51brain metastases and other non
44:53cancer indications like trigeminal
44:55neuralgia for example.
44:56These are just two case studies
44:58from our practice.
44:59This is a 56 year old female with
45:01a grade one meningioma who had
45:04a wonderful section but wasn't
45:06safe to remove all of it and so
45:08we're able to come in with their
45:11ultra precise novelis exact track.
45:13Approach and using a rapid or
45:14conformal plan that we generated
45:16you can see here the dose outline
45:18that we're able to avoid a lot
45:20of very critical structures,
45:21such as things like the optic apparatus
45:23as well as other parts of the brain.
45:26So this is really a very useful technique,
45:28and again a framless approach
45:29for precision radiation.
45:30Here is just another example
45:32of how we use the gamma knife,
45:34and this is brain metastases.
45:35This is a 64 year old female with a
45:37new newly diagnosed non small cell
45:39lung cancer who was found to have
45:42brain brain Mets at the time of diagnosis.
45:44When you look at the scan you
45:46would you immediately think that
45:47this patient needs to go to whole
45:49brain radiation therapy.
45:50This for the clinicians in the room,
45:52and certainly that would be a
45:54reasonable approach for this patient.
45:56But recognizing the amino therapies and
45:57all the targeted therapies question
45:59is whether we could treat with a
46:01more focused approach if there is a
46:03chance for longer survival for this patient.
46:05And that's exactly what we did.
46:06This is a case from doctor Chang
46:08or chain went in and just as doctor
46:10maternus present that wonderful
46:11case earlier of a lesion that was
46:14affecting the speech shown here.
46:15And then a large lesion causing
46:17a lot of Mass Effect, shown here.
46:19She was able to reset those critical lesions,
46:21and that's again shown by the arrows
46:23and then actually use that frame
46:25based single fraction gamma knife.
46:27So single fraction radiation to the
46:28smaller lesions that were there as well
46:31as the cavity of the respected area.
46:32But recognizing these other
46:34areas need to be treated like
46:35this and this,
46:36but their larger were then able to.
46:38She was then able to use the icon
46:40system to deliver 5 fractions
46:42in a hypofractionated manner
46:43to some of these other areas.
46:45Where would be more safer to use that?
46:47So really an excellent.
46:48Example of how we use all these
46:51new modalities to really push
46:52the envelope and what we can do
46:55for patients with brain tumors.
46:56This is just for the clinicians in the
46:58room showing the dose distribution.
47:00We get very very nice dose drop
47:02off using this this approach.
47:04So moving along.
47:05Just want to tell you a little
47:07bit about Proton Therapy again
47:09recognizing their patients as well
47:11as caregivers on the call tonight.
47:13So protons are a fascinating
47:14modality as some of you may know
47:16convectional entered xrays which
47:18we use for most of our patients.
47:20A really good and I showed you
47:22those focused plans of treating
47:23the tumor over the normal tissue,
47:25but they still have something
47:26we call exit dose and that's
47:28shown by the tumor area here.
47:29But the exit dose for the
47:31radiation doesn't stop.
47:32Protons have something very
47:33fasting called a Bragg Peak,
47:34and essentially you're throwing dose
47:35at the tumor in it stopped right
47:37at the edge of that tumor margin.
47:39OK,
47:39and just showing you that again
47:41that the different with the
47:42more schematic of a patient.
47:44You can see a little bit
47:45of exit dose for the tumor.
47:47But then when you have a
47:49proton based approach you have.
47:50Complete drop off of the dose of
47:52very very nice to add advantages
47:54for a variety of tumors.
47:55In particular,
47:56I'm one of the pediatric brain
47:58tumor doctors radox here and this
47:59is a plan what we call crane's
48:01final radiation and this is a
48:03pediatric megill blastoma and this
48:04is our normal conventional plan.
48:06This is the standard of care and
48:08you can see there's a lot of exit
48:10dose here and at first glance you
48:12think maybe just the abdomen would
48:14be at risk but you can see here.
48:16Actually it's the heart that we worry
48:19bout for patients that could live for.
48:215060 years depending on their age
48:23and using proton based radiotherapy
48:24you can see that we're able to
48:27completely stop the dose into
48:29those critical structures,
48:30and this is a slide from doctor Ken Roberts,
48:33who leads who's leading our proton
48:35plan development plan in Connecticut,
48:37along with other folks.
48:39So where are with protons?
48:40So just at one slide to show
48:42that it is coming soon we have
48:45a certificate of need that's
48:47been filed or about to be filed.
48:50Rather we believe that within about
48:5221 to 24 months will have the IBA.
48:55Proteus one.
48:55This is one of the state of the
48:57art pencil beam scanning Proton.
48:59I am RT devices will be able to
49:01offer that and we're doing that
49:03in collaboration with the folks
49:04at Hartford Healthcare.
49:05So do stay tuned really excited
49:07about these developments.
49:08In the meantime though,
49:09we have a lot of patients that will need
49:12Craignish final radiation of various ages,
49:13and they might not be able to go up to a
49:17proton facility in New York or Boston.
49:19We certainly send them when we can,
49:21and at yeah, what we've been
49:22able to do a recently.
49:24Really this is Ken Roberts in our Department.
49:26Has developed a protocol for V Matt
49:28Rapidarc Crane, Espona radiation,
49:30and this essentially using those photon
49:32plans that I showed you earlier and
49:34using the dynamic arc to sculpt the beam,
49:36and this is what a conventional Crane is.
49:38Final plan would look like
49:40like I showed you earlier,
49:42but using the map you can see we
49:44actually get a pretty good sparing,
49:46although we have a lower dose path
49:48that I'm not showing you here,
49:50but certainly better than the
49:51alternative the conventional approach.
49:53So we're using this quite actively
49:54in patients and and certainly
49:56feel free for the clinicians.
49:58The radiation Oncologist to reach out to us.
49:59If you have a case that you.
50:00Be interested in discussing with us.
50:02This is a case of a 25 year old female
50:05with VM who had a local recurrence
50:07but unfortunately had left him in a
50:09jewel spread throughout the tumor.
50:11Studying this fine and we're actually
50:13able to design quite a nice crane
50:15spinal vemap plan and this is also
50:17shown with for the rat and the plan
50:19some for the original radiation.
50:21There is shown in the heat map
50:24so again really.
50:26Lot of flexibility in the way that
50:27we use this technique for a number of
50:30cancers and certainly just reach out to us.
50:32If you're interested.
50:33Finally,
50:33the last two minutes just want to
50:36show you where we're headed now
50:37with some of the bench to bedside
50:39research that we're doing and we
50:41don't have time for this today.
50:43But our laboratory is very interested
50:44in developing novel Therapeutics
50:46for the treatment of gliomas.
50:47Another brain tumors,
50:48and we've been very lucky to
50:49publish some exciting work,
50:51shown here in the left in nature
50:53and some other journals,
50:54but more importantly than
50:55able to translate that.
50:56Directly into clinical trials,
50:57and as you can show,
50:59highlighted in red,
51:00a number of them for brain tumors law.
51:02This work comes from the groups here at Yale,
51:05including Moroccan L Peter Glaser
51:06and others shown here,
51:08and in particular there is one study
51:10that would may be of great interest to
51:12the brain tumor folks on the call today.
51:14This is a study testing a novel DNA repair,
51:17a neighbor called a parp inhibitor,
51:19combining with Tim's omide
51:20chemotherapy for patients with Idh,
51:21Mutant Recurrent Glioma.
51:22And this is based on our laboratories work.
51:25This is a trial that I run
51:27with doctor David Shift.
51:28And 20 euro is one of the eyes as well.
51:31We have actually just finished the dose
51:33escalation phase actually this morning,
51:34so we are now entering the
51:36phase two component and
51:37certainly would.
51:38Would love to hear from folks.
51:39If you have a patient,
51:41call doctor Romero or myself with that,
51:43certainly just email me, you know,
51:45just want to give you a brief
51:46kind of smatter of what we're
51:48doing down in Smilow rad onc.
51:50Email me check out check out on
51:52Twitter store up to in the laboratory
51:54and also you can come to our website
51:56and again thanks for joining us.
51:58This evening is really great
52:00to see so many participants.
52:01I'll leave it at that.
52:09Thanks for indeed and then. Finally,
52:10we're going to hear from Doctor Amoro,
52:13who is cheap of neuron cology.
52:38Thank you everyone for a sustained
52:40this later to talk about brain tumors.
52:42It's really a pleasure to be part
52:44of this great meeting and to chat
52:46a little bit about what's going on
52:48in terms of clinical trials and
52:51Translational research in our field.
52:54Here by disclosures,
52:55I declined to try this for a living,
52:58so I have contacted many companies and
53:01work with many companies in terms of
53:04research support and these are companies
53:07that for which I provided advice.
53:14So we have only a few minutes,
53:17but I would like to give you a
53:20broad overview of what's going on
53:23in which direction the field is
53:26heading in the next few years.
53:28So of course the first major advancing
53:31our field was the availability of
53:33gene sequencing to guide this in
53:36terms of diagnosis and in terms of
53:39potential experimental treatments.
53:40So doctor Blanding has already
53:43alluded to this,
53:44but the reality is that we are dealing
53:46with a brain tumors that are extremely
53:49heterogenous from a genomic standpoint.
53:51So what you're seeing here is
53:54all gliomas and what you can see
53:56is that there are very distinct
53:59signatures depending on the type of
54:01the tumor that we are dealing with.
54:03So that starts with algorithms that
54:05have a very typical signature of
54:08Ideating Tation when connecting
54:09you collision turned promoter.
54:11see I see and if you could be one mutations.
54:15And that is in contrast with our global
54:18storms that have EGFR mutations.
54:21Petan CD K mutations and MDM 2.
54:24So this is great for diagnosis and we
54:27certainly use this in clinical practice.
54:30But the question is how to translate
54:33this into therapeutic advances.
54:35So doctor bowling has already
54:37alluded to this a little bit,
54:40but the reality is that only a
54:42very small proportion of these
54:45mutations are actually druggable.
54:47So what you're seeing here is the
54:49same of those patients now divided
54:52into whether there was an actionable
54:55mutation or not.
54:56And here,
54:57looking at the percentages of these patients,
55:00and as you can see,
55:02low hanging fruits for example,
55:04be representation.
55:05Is only present about 1 to 2% of
55:08the patients and same thing goes
55:10for all of these other mutations
55:12that for which there are potentially
55:15available treatments.
55:16But they are very challenged to
55:19study Becausw.
55:20Again,
55:20these pages are spread out sometimes
55:22in the community.
55:24Sometimes we don't get to us and it
55:26is hard for us to deliver clinical
55:29trials for these specific communications.
55:32Course low hanging fruit is age wanted,
55:34Mutation and a doctor Bender over.
55:37Already eluded to that as one of the
55:40very important mutations that can be
55:42potentially targeted in various ways,
55:44but for the most part the other mutations.
55:47It remains very challenging to run
55:50clinical trials that are specific for them.
55:53One trend nowadays is actually
55:55conducting what we call basket
55:57trials where patients are enrolled,
56:00selected by limitation and not
56:02by the disease itself,
56:04which means that patients can be
56:07enrolled in a trial together with breast
56:10cancer with lung cancer and prostate cancer.
56:13Unfortunately,
56:14in our case,
56:15a lot of the trials do exclude
56:18patients because of brain tumors.
56:21The brain tumor location exclude them.
56:24Property is being destroyed,
56:25so we have to do a lot of lobbying
56:28with their companies to really push
56:30for basket trials that actually
56:32allow our patients to be enrolled.
56:34Fortunately for us is that
56:35we have a very strong phase.
56:38One group here at Yale,
56:39and we're able to find trials.
56:41And if we don't find trials,
56:43we do make every effort to contact
56:45the drug companies and see if
56:47they can provide this drug on
56:49a compassionate use protocol.
56:53Another challenge that we are facing
56:56now is that while this is all great,
56:58but the sequencing is typically done at
57:01the time of diagnosis and here you're
57:04looking at several potentially actionable
57:06mutations on this patient that had a.
57:08An astrocytoma and this patient was
57:11treated successfully, if initially,
57:12but then the patient had a small
57:15recurrence and a lot of Physicians would
57:17not ask for surgical resection here.
57:20But because this patient had a
57:22very good course and this was
57:24a very favorable location,
57:26we convinced our students to go after this
57:29and what we found is that all of those
57:32potentially actual rotations were all gone,
57:35replaced by passenger mutations
57:36that are not relevant,
57:38and what was driving the malignancy
57:40here was really.
57:42Edges in the economic landscape.
57:44So this makes our lives a little harder
57:46because it can imagine that we're trying
57:49to enroll these patients in targeted
57:51therapies based on this type of Mutation.
57:54But the reality is that what we
57:56really need is to have an update.
57:59Information on the genomics so we can match
58:03these patients in a more efficient way.
58:06So here is just the summary
58:08of where we heading,
58:10right?
58:10So I think right now one of our major
58:13focus is really on phase zero tries
58:16and what this means that we're trying
58:18to give drugs to the patient and then
58:21respect the tumors and then have more
58:24information on what kind of targets
58:26our new treatments are really hitting
58:28and whether there really are doing
58:30the job that they are supposed to do.
58:33The other trend that I just
58:36alluded to was the basket trials
58:39that are getting more and more.
58:42Efficient,
58:42but it also again carries the challenge
58:46of excluding patients with brain tumors.
58:50And then again,
58:51the other trend right now is to
58:53really re sample recurrent disease
58:55if that's really important.
58:57So one of the applications is really to
58:59exclude the hyper mutator phenotype,
59:02which doctor Brownlee has already alluded to.
59:05And again, as I mentioned,
59:07to update the gene sequence,
59:09see another trend right now is to
59:11target what we call trump commutation.
59:13So these are mutations that are that
59:15arise early in the uncle genetic
59:18process and they are very conserved
59:20throughout the history of the disease.
59:22And these materials are not so
59:24easy to target.
59:25This depends a lot of what
59:28we call functional genomics.
59:29So studies that define vulnerabilities that
59:32are associated these mutations and that
59:34is one of the paradigms that Doctor Bindra.
59:37To develop his trials in Ideating Tations.
59:40So,
59:41and overall what the field is actually
59:44doing as a whole is actually moving
59:47out of these very selected targets to
59:50alternative strategies that are more
59:53stable in the course of the disease.
59:56So one of them is immunotherapy
59:59and Doctor Bob.
01:00:00Already sore eyes to you that
01:00:04unfortunately image checkpoint inhibitors
01:00:06have largely failed in Glioblastomas.
01:00:09There is many reasons for that and
01:00:11we are trying to understand that we
01:00:14published the first study of magic
01:00:17when inhibitors using volume AB and
01:00:19it alone map over four years ago and
01:00:22there has been a lot of advance in
01:00:25trying to understand how the brain
01:00:27handles the immuno logic system in a way
01:00:31that is both protective of the brain.
01:00:34But unfortunately also protective of
01:00:36the tumor. So to study this further,
01:00:39what we did was to enlist specialists
01:00:42in the immune system in the brain.
01:00:45So a lot of the work in cancer
01:00:48is done by Immuno colleges.
01:00:51But we're fortunate enough to have
01:00:54at Yale access to amazing Nero.
01:00:58Inflammation near inflammation
01:00:59specialist if you will,
01:01:01and one of them is doctor David Hafner
01:01:03who studies inflammatory disease in
01:01:05the brain and his hypothesis is that
01:01:09a more relevant checkpoint in the
01:01:11brain is this normal ethical digit.
01:01:13So this is a novel immune checkpoint
01:01:16that seems to have a very important
01:01:19role in the central nervous system.
01:01:21For example,
01:01:22it is lacking in patients that have
01:01:24multiple sclerosis and expression of
01:01:27digits is very frequent in Glioblastomas.
01:01:29So to investigate this further,
01:01:31we partnered with Doctor Moliterno
01:01:33and doctor David has first lab
01:01:36with Liliana Luca and orders.
01:01:38And what we're doing is national trial,
01:01:41multicenter led by Yale that
01:01:42will randomize spaces that are
01:01:44candidates for surgery for either
01:01:46receipt and tactician antibody.
01:01:48Anti PD,
01:01:48one antibody and package it
01:01:50plus anti PD one antibody,
01:01:52oropos IBO and that is just before
01:01:55the surgery after the surgery.
01:01:57All of the pieces will have
01:01:59access to both the combination
01:02:01of Anti Tigit and anti PD one.
01:02:04And what we're going to do is to really
01:02:08look at these tumors and paired blood
01:02:11samples and perform state of the art.
01:02:14Translational studies,
01:02:14including single cell RNA sequencing
01:02:17utilizing the next onomics at the
01:02:19youth center of genome analysis.
01:02:21So this is very exciting.
01:02:23Troy,
01:02:23that will actually tell us where the
01:02:25pieces are really mounting effectively.
01:02:28Motor responses in the brain,
01:02:30and we hope to learn a lot about
01:02:33whether this hypothesis is correct.
01:02:35And hopefully these spaces will
01:02:37also benefit from the fact that
01:02:39these drugs are being given in the
01:02:40what we call new edgmont setting.
01:02:45Our another trend is to perform studies
01:02:48in parallel with the clinical trials,
01:02:51and in this particular case what
01:02:54we're going to do is to study these
01:02:57drugs in a more systematic way by
01:03:01utilizing genetically engineer mice.
01:03:04So these are models developed by doctor
01:03:07city chain that has these amazing
01:03:10technologies to really create what we
01:03:12call patients avatars so basically.
01:03:15These are mice that will develop
01:03:18tumors that resemble certain patients
01:03:20so that we get the combination of
01:03:23mutations and then he creates these
01:03:26models utilizing a crisper technology
01:03:28and then we will treat these animals
01:03:31with the same types of combinations to
01:03:34see how these novel agents behave in
01:03:37the setting of the different mutations
01:03:40that are associated with these tools.
01:03:43So this is very exciting work.
01:03:46That, again is going parallel.
01:03:47That will inform us the clinical
01:03:49Troy and then hopefully help us
01:03:51select patients in the future.
01:03:52There are more likely to benefit
01:03:54from each of these treatments.
01:03:58Another clinical trial coming up in
01:04:00generate is coming from this company
01:04:02called Nuna Pharmaceuticals and what
01:04:04they did is that they discovered
01:04:07another receptor within the Alpha V
01:04:09Beta three integrin that is started
01:04:11by this new drug called FB PMT,
01:04:14and this has an amazing activity
01:04:17in term cells into mark environment
01:04:19and into Genesis and will have
01:04:22the 1st in human trial here at AO.
01:04:24And once again we are conducting.
01:04:27Laboratory experiments in parallel
01:04:29as we develop that Royal to try to
01:04:32understand this drug a little bit
01:04:34better in terms of what it does to
01:04:37some invasion for the formation.
01:04:38Activation of the signaling networks and
01:04:40gene expression for terms and Phosphate.
01:04:43Omics studies to see if we can again
01:04:46identify who are the best candidates for
01:04:49this type of treatment and also identify.
01:04:52Which are the best partners to be
01:04:54combined with this drug in the future?
01:04:56And this is all work being done by
01:04:58Doctor Underlift Chanco here at the air.
01:05:03Another superstar laboratory scientist
01:05:05here at Yale is Doctor Iwasaki.
01:05:08Some of you may have seen her immediate.
01:05:11She's our COVID-19 specialist,
01:05:13so she's all over.
01:05:15And in fact this is catching her
01:05:18attention from her work in brain tumors.
01:05:21But she is very interested in developing
01:05:24novel treatment for global stoma because
01:05:27of her interest in the immune system
01:05:30in the brain and with work done by
01:05:33Eric Song and Jonathan's in her lab.
01:05:37In a very hyper 5 paper
01:05:40published in nature of this year,
01:05:43she found that really one of the
01:05:46problems of the immune system
01:05:48activation in the brain is actually
01:05:51linked to the lymphatic drainage
01:05:54that is very defective in the brain.
01:05:57And then she discovered that with Vejer
01:06:00C she could potentially modulate this
01:06:03and then eventually they patients started to.
01:06:07For the personal did mice started
01:06:09to respond to the email checkpoint
01:06:11inhibitors and other forms of women
01:06:14of therapy so she started killing mice
01:06:17by adding the jeffsy to the male therapist.
01:06:20So this is very exciting work that
01:06:24we hope to be translating into a
01:06:27trial in the near future.
01:06:29Doctor Bender already alluded
01:06:30to his work in DNA repair.
01:06:33Yale has a long tradition of
01:06:34work done in this space effect.
01:06:37A lot of the very early studies
01:06:39were actually done here,
01:06:41and after being there,
01:06:42continue with that tradition and launch it.
01:06:45A bunch of colon trials looking at
01:06:47Parp Inhibitors in I DH mutant gliomas.
01:06:52Also, going on here is expanding
01:06:54on some of the work on DNA repair
01:06:58and extended to MDM two inhibitors.
01:07:00We have partnered with Mayo Clinic to
01:07:03develop 2 early phase clinical trials.
01:07:05One will be. Investigating MDM,
01:07:09two inhibitors and the other one
01:07:11will be that is led by general care
01:07:14animal Glennis at Mayo Clinic in in
01:07:17partnership with us and doctor Bender
01:07:19and I will be working on a project
01:07:22to develop ATR and ATM inhibitors and
01:07:25this is again very exciting work and
01:07:28we are fortunate to have bachelors
01:07:30who is also a DNA repair specialists
01:07:33when it comes to drug development
01:07:36and this is a really exciting.
01:07:38Development here at Yale.
01:07:42And we don't have time to
01:07:44go over all of our trials.
01:07:46But here is just a non exhaustive
01:07:49list of what's going on.
01:07:51We also have inhibitors of ID,
01:07:53age mutant for low grade gliomas,
01:07:55with the idea that if we intervene
01:07:57in this tumors earlier when they're
01:08:00not behaving in a Malignant Way,
01:08:02maybe these drugs are more effective.
01:08:04We have drug combinations
01:08:06for beer affix extender,
01:08:07E mutations in Bloom's credit for
01:08:10germs and all other brain tumors.
01:08:12Doctor Blanding already alluded
01:08:14to red grafted,
01:08:15and how that could potentially
01:08:17improve survival in newly diagnosed
01:08:19and recurrent your games,
01:08:21and this is an ongoing trying
01:08:23that's really exciting.
01:08:24We're exploring another potential
01:08:26prior with interest or and and this
01:08:29is 4 pieces that have a germline
01:08:32by market called the GM one.
01:08:34So again,
01:08:35trying to deliver on this promise
01:08:37of personalized medicine.
01:08:38This is a drug that could potentially
01:08:41help patients that have this.
01:08:43Buy a market.
01:08:44Where is the page that do
01:08:46not have the biomarker?
01:08:48Do not seem to respond so this
01:08:50is another potential concept
01:08:52that we will be exploring.
01:08:54We have chemotherapy regiment
01:08:55trials for one painting.
01:08:57Q Coleader argument.
01:08:58Gliomas have petition driven controls for
01:09:00brain metastasis and for meningiomas,
01:09:02so this is all happening right
01:09:04here at you and we hope to see
01:09:07more and more patients in growing
01:09:09our clinical trials so we can
01:09:11advance the field and try to match.
01:09:14These patients,
01:09:15with the best experimental treatment
01:09:17available and we are very fortunate
01:09:20to have all of these people working
01:09:23across multiple scores here at the
01:09:26that will be helping us to really
01:09:28make a difference in this space.
01:09:31Thank you very much for your attention.
01:09:41Yeah, so we will open this up to questions.
01:09:47Then I guess what we could do is if
01:09:50you want to submit any questions to the
01:09:54chat and then I can just read them off.
01:09:59Was the Q&A. Then there's
01:10:01the separate bubbles. Oh, I
01:10:03see that. Yeah, yeah, yeah.
01:10:06So OK, so there's two questions on Q&A,
01:10:09so that's where we can
01:10:11work with the questions.
01:10:13So first, does dexamethasone
01:10:15contribute to tumor growth?
01:10:19Nicola, I can take on that
01:10:21question, so I think that's an excellent
01:10:24question and that is something that
01:10:27people have asked for a long time.
01:10:30The concern came from the
01:10:32literature in prostate cancer,
01:10:34where many preclinical studies were
01:10:37done raising concerns about the use
01:10:40of steroids and how they could have a
01:10:43detrimental effect on tumor growth.
01:10:45So in gliomas this has not
01:10:50been so clear we dislike.
01:10:54Spirit becausw of the many side effects,
01:10:58particularly proximal myopathy.
01:11:02Increase in hyperglycemia.
01:11:03In fact, hyperglycemia itself is
01:11:06a well known factor that actually
01:11:09induces tumor growth and is
01:11:11associated with the worst prognosis.
01:11:13So it wasn't an indirect effect,
01:11:16but not necessarily a direct
01:11:19effect of the steroids.
01:11:21But in terms of direct effects on the tumor,
01:11:24we were sort of reassured by
01:11:27the literature on Avastin.
01:11:29And that is the cause.
01:11:30People who receive the vast
01:11:32and use less spirits,
01:11:33and yet they did not live longer than
01:11:36patient that actually were on the control
01:11:38arms and receive a lot of steroids.
01:11:41And then they lived just as long.
01:11:43So that's sort of reassuring in terms
01:11:45of that is not having a direct effect.
01:11:48But again,
01:11:49steroids have lots of other
01:11:50and Intendant side effects,
01:11:52and we try to avoid the use of those.
01:11:56And I think the IT is a huge
01:11:59issue for us if we want to develop
01:12:02successful immunotherapy's.
01:12:03So that is potentially the main
01:12:06issue right now with the steroids.
01:12:08Patients with that are on high
01:12:10dose of steroids.
01:12:12They're basically excluded
01:12:13from immunotherapy trials.
01:12:16And of course, from a surgical perspective,
01:12:19wound healing is always a concern.
01:12:23OK, on to the next one.
01:12:26Is there any investigation of
01:12:28the utility of hypo methylating?
01:12:30I think that is agents in neurooncology.
01:12:36I'm in love.
01:12:37Those have been studied in the past,
01:12:39and the studies were not successful.
01:12:43It was some years ago even.
01:12:46I can't remember the name of
01:12:48the name of that product,
01:12:50but the theory was to induce
01:12:52methylation with another drug
01:12:54and it just didn't seem to
01:12:57alter outcomes for patients.
01:12:58Not sure doctor Moreau,
01:13:00if you recall more about that product.
01:13:03Well, there's a host of.
01:13:07Preclinical data on days,
01:13:08particularly in I DH mutant tumors,
01:13:11I think the jury is still out.
01:13:14I have used some of these agents off
01:13:18label and I have not seen responses,
01:13:21but the reality that good clinical
01:13:24trials that are more informative
01:13:26have not been conducted especially
01:13:28selected for ideating mutations,
01:13:31and I can also that doctor Bender comment
01:13:34on this wonderful question.
01:13:36There was a trial with Vorinostat
01:13:39and radiation led by the NCI.
01:13:41It was not randomized.
01:13:42Had had some good results but
01:13:44really wasn't robust enough
01:13:45to move forward and start.
01:13:47Romero mention the Vid.
01:13:49HD methylating story is really
01:13:50unfolding in the AML world.
01:13:52There's a lot of interesting
01:13:54combinations and I do believe
01:13:56it will be making its way up
01:13:58in the context of combination
01:14:00therapies is certainly more
01:14:01to learn too.
01:14:05OK, next question. Have you had any
01:14:08experience with personal vaccines?
01:14:15Well, I can comment on that,
01:14:18so I think vaccines are working for us.
01:14:23The majority or most all of the vaccines
01:14:26have not been out in randomized trials
01:14:29and welcomed up to randomized trials.
01:14:32So I've done several trials of those,
01:14:35including the Greek salad
01:14:37scenes from the same patient.
01:14:40There are trials now that runs are
01:14:43getting better and more sophisticated,
01:14:46but vaccines by themselves are still
01:14:49to find a niche in College in general.
01:14:54Unfortunately,
01:14:54most of the trials have been negative,
01:14:57so I think vaccines may be part
01:15:00of the answer in the future.
01:15:03But on their own. It is going to be again.
01:15:08It's a work in progress.
01:15:11My thought is to be very complex to make the
01:15:14vaccine product was involved with a study
01:15:17to develop a heat shock protein vaccine
01:15:19from tumor tissue like say an it was just a
01:15:23very complex product to generate the vaccine.
01:15:26Then the second issue being even if
01:15:28the vaccine is generated successfully,
01:15:30there can be factors within the patient that
01:15:33inhibit the vaccine from working effectively.
01:15:36We don't understand really what those are.
01:15:38Probably the biggest vaccine
01:15:40story is a vaccine against.
01:15:42EGFR V3 called Rindopepimut,
01:15:43which seemed to have great
01:15:45data in earlier studies.
01:15:47Phase two studies and then,
01:15:49when studied in the pivotal
01:15:51trial phase three,
01:15:53appeared to be completely
01:15:54ineffective to improve survival
01:15:56of patients with the biomarker,
01:15:58and it's still unclear to me.
01:16:02What exactly the factor is?
01:16:04And it's probably a number of
01:16:06factors related to the G BM
01:16:08suppressed immune microenvironment.
01:16:13OK. Next question,
01:16:16will it be possible? I just lost it.
01:16:18Will it be possible to use protons on a
01:16:22meningioma that's in the cavernous sinus,
01:16:24which is next to the pituitary gland in
01:16:28the optic nerve from a surgical perspective,
01:16:30few things I would comment on
01:16:32and then Ranjeet can comment.
01:16:35So these primarily sphenoid wing really
01:16:37meningiomas or skull base meningiomas
01:16:39were actually in the process of studying
01:16:42them and those were some of the ones.
01:16:45Where the genomic driver mutation can
01:16:47really determine how we treat them,
01:16:50or at least how we use it in our tumor board.
01:16:55So sometimes depending if there's
01:16:57a component of that tumor that's
01:16:59a little bit more exophytic that
01:17:01can be surgically accessible,
01:17:03we will advocate for the removal
01:17:07of part of that.
01:17:09Also one option as well,
01:17:11which we have done too is if
01:17:14the optic nerve is nearby.
01:17:16If we can decompress the optic
01:17:19nerve from a surgical standpoint.
01:17:22That can help preserve vision or
01:17:24even have the return of vision.
01:17:26I actually did a case like that
01:17:28just a few days ago last week and
01:17:31then also that can help preserve
01:17:33the vision in the other side,
01:17:36so usually at least in our in our hands
01:17:39we like to exhaust all the options,
01:17:42understand the tumor from a
01:17:44genomic standpoint for ones that
01:17:46clearly don't need surgery.
01:17:48I think we way different factors into
01:17:50when we radiate or or don't radiate.
01:17:53You know in terms of the patients
01:17:55age and follow up and growth and
01:17:57symptomatic and that sort of thing.
01:17:59But I do think genomics plays a big role
01:18:02in the Genomic driver of the tumor.
01:18:05Rinji
01:18:05Yeah, it is really really great question
01:18:07and actually your response highlights
01:18:09what's great about the institution.
01:18:11We have such a close relationship
01:18:13with all members of the neurosurgery
01:18:15neurology radiation oncology team talking
01:18:17about what is the best modality and.
01:18:19And often you know we start with
01:18:21surgery and if radiation is needed,
01:18:24you can think about things like the icon in
01:18:26the gamma knife that we talked about earlier,
01:18:29which actually has the same
01:18:31dose distribution as Protons And
01:18:32if not fractionated radiation.
01:18:34And the question there is whether
01:18:36you would need protons most of the
01:18:39times we don't feel there is a need.
01:18:41If the patient needs radiation
01:18:43we can do quite well with gamma
01:18:45knife or using our regular Linux,
01:18:47so to speak, but there are certainly
01:18:49cases we send to referral for protons.
01:18:52So wonderful question.
01:18:56In wonderful response,
01:18:57can supplements like antioxidants
01:18:59etc be used during radio and chemo
01:19:03treatment that are there studies that
01:19:06suggest a possible beneficial outcome?
01:19:13Vitamin C can avoid the
01:19:14biggest issue is that.
01:19:17Studies and supplements are.
01:19:20Difficult to study, some maybe.
01:19:23Plant based or botanical products
01:19:25which are even more complicated
01:19:28to study than Pharmaceuticals.
01:19:30So there really is no great data behind.
01:19:35Of these studies,
01:19:36unfortunately behind you know,
01:19:38except for some limited
01:19:39lab or preclinical data.
01:19:40So in terms of using supplements
01:19:42and my personal practice,
01:19:44I do have some patients that
01:19:46are interested in supplements
01:19:48and opt to use them,
01:19:49and I help guide the patient
01:19:51to make sure that the use is
01:19:53what I consider to be safe and
01:19:56not detrimental to the patient.
01:20:00Yeah, I would add that.
01:20:01Certain supplements actually may
01:20:03result in worse outcomes and this has
01:20:06come out in many studies in the past.
01:20:09I think in terms of antioxidants,
01:20:12I think they are.
01:20:14But is not recommended during
01:20:16the radiation and I can defer to
01:20:19doctor Bender to comment on that,
01:20:21but typically high dose
01:20:23of anti oxidants is our.
01:20:25Typically not preferred during the radiation.
01:20:30Yeah, we always get a little bit
01:20:32worried because the way the vitamin C,
01:20:34the structure and Whatnot is,
01:20:36it's it's a free radical Scavengers.
01:20:38We've sort of alluded to,
01:20:39and so it can actually block
01:20:41the effects of radiation
01:20:42on tumor damage so. No,
01:20:44say it's true. 'cause he always
01:20:46stops the vitamin C that I put
01:20:49my patients on after surgery.
01:20:51And I don't argue. I think
01:20:54for long-term patients
01:20:56that are using supplements.
01:20:59You know, it's unclear to me
01:21:01that these are detrimental,
01:21:02but perhaps they could be
01:21:03beneficial to select patients.
01:21:05But again, we can't tell prospectively
01:21:07who will benefit from these.
01:21:09Yeah, it's just that's an important
01:21:11factor to keep in mind when
01:21:13considering any kind of supplement and
01:21:15gender somebod 2 chat questions
01:21:17just to oscillate back.
01:21:18I see quite interesting as
01:21:20do the other questions too.
01:21:22Alright, so will
01:21:23make these are last.
01:21:24It looks like 5 total,
01:21:26so given there is a significant number
01:21:28of tumors who have the TP 53 mutation,
01:21:31are there any current or upcoming
01:21:33trials that target this?
01:21:34And Mike also said thank you,
01:21:37so thank you.
01:21:40So yeah, I'll take that.
01:21:42It is interesting that given some of
01:21:45these mutations that are so common
01:21:47that we haven't had a therapy,
01:21:49there are trials in development
01:21:51targeting a related protein called MDM.
01:21:53Two or MDM two inhibitors which
01:21:55actually act in this same pathway.
01:21:57So I think surprisingly,
01:21:59there's not been enough.
01:22:00It's been difficult to target
01:22:02that Mutation 50% of all cancers
01:22:04actually have this mutation there,
01:22:06certainly new therapies around
01:22:08the bend that are trying to.
01:22:10Attack this axis. Yeah,
01:22:13there are some compounds that are entering
01:22:16clinical trials that are mutant P53
01:22:19reactivating compounds and but again,
01:22:22there are initial stages of clinical trials.
01:22:26And then we'll see if that pans out. Next,
01:22:32is there any potential benefits of
01:22:34starting the optune immediately following
01:22:36radiotherapy instead of waiting until TM Z?
01:22:39Is there any proven benefit for
01:22:41patients that wear it more than the
01:22:45recommended 18 hours a day? Nick, so
01:22:48in the pivotal trial,
01:22:49optune was initiated four to
01:22:51seven weeks after completing
01:22:52radiation and then used with that.
01:22:54Amazon might cycles and could
01:22:56be continued actually until the
01:22:58second progression for a patient.
01:23:00So that's the current
01:23:01indication for the device.
01:23:03There have been 2 pilot studies
01:23:05done where option was initiated
01:23:07at the start of radiation,
01:23:09and patients use the device.
01:23:10Actually during radiation
01:23:12treatment and following.
01:23:13And those seem to indicate some
01:23:16benefit to starting out too.
01:23:17That way without additional skin toxicity,
01:23:19so a large phase three study is
01:23:22planned to test this hypothesis.
01:23:24Starting optune at the beginning
01:23:26of radiation versus at the start
01:23:28at the end of radiation that should
01:23:30be starting up next year and
01:23:32then in terms of treatment usage,
01:23:34there is actually incremental benefit,
01:23:36so the more a person is able to utilize it,
01:23:40the better the average survival
01:23:42would be for a patient,
01:23:43particularly those that can.
01:23:45Steve above 90% usage month to month.
01:23:48They had a longer survival time than
01:23:50patients that had less usage in the
01:23:53pivotal trial. Yeah, the caveat.
01:23:56Taking
01:23:56skin toxicity.
01:23:57Patients cannot do that,
01:23:59and it's really difficult for them
01:24:02to use optune 100% of the time.
01:24:06So it is a cumbersome device.
01:24:10Then it is very individual.
01:24:12I mean the choice of using the
01:24:15device and how that impacts their
01:24:18quality of life is very personal.
01:24:21Many patients choose not to go
01:24:23that route and that is the cause
01:24:26we don't see themselves bearing
01:24:28that device 100% of the time.
01:24:31So unfortunately the clinical
01:24:32trials were not properly designed.
01:24:35That led to the approval
01:24:38and basically there was no.
01:24:41In in that phase trial,
01:24:42the control arm was not blinded
01:24:45and there was no sham device which
01:24:48would be the best control for this
01:24:51type of try and that was not done.
01:24:53But in any case,
01:24:55the evidence points that
01:24:57there could be some activity.
01:24:59And some patients choose to
01:25:01use and others prefer not.
01:25:03To use most clinical trials.
01:25:05They do not allow for the
01:25:08concomitant use of up to.
01:25:10OK,
01:25:12next.
01:25:14If unable to access the nurse
01:25:16surgical care team on our case,
01:25:18receiving care from a team in another state,
01:25:21and we're putting an emergent situation
01:25:23like an extended seizure, for example,
01:25:25would it be best to admit to an ER within
01:25:28a hospital that has a functional MRI?
01:25:30Should I make that a priority while
01:25:32waiting to see if stabilization and
01:25:34transferred to care team as possible?
01:25:36I'm a caregiver so, you know,
01:25:38this is a difficult situation in that most
01:25:41most patients and care providers don't
01:25:43know or care Givers rather don't know.
01:25:46What they're what they're necessarily being
01:25:48told and and and you see a neurosurgeon and
01:25:51this neurosurgeon sounds pretty capable,
01:25:54an incompetent and so you
01:25:55don't really know Ann.
01:25:57You're a lot of times patients I see
01:26:00two are being told that you know
01:26:02this is emergent surgery and rushing
01:26:05to surgery and that sort of thing.
01:26:08What I always say is, it's really important,
01:26:11I think, to get second opinions.
01:26:13Of course you know if it's life or death,
01:26:16that sort of thing.
01:26:18You don't have that luxury.
01:26:20Having said that, most tumors are not.
01:26:25Immediately life or death,
01:26:26and so there there can be some time,
01:26:29typically to consult with an
01:26:31academic centers such as ours,
01:26:33even if it is a long distance away.
01:26:36We frequently have those calls or emails
01:26:39or consultations and so then you can
01:26:42understand what what you're up against
01:26:44and what the recommendations would be,
01:26:46even if it's not realistic for traveling.
01:26:49But I would always suggest making sure
01:26:52an asking numbers to you know how many.
01:26:55Surgery is just the does the
01:26:57neurosurgeon perform a year.
01:26:59But how many brain tumor
01:27:00surgeries does he or she perform?
01:27:02And is this what he does?
01:27:04Or is he a general neurosurgeon?
01:27:06Does he do spine or surgery etc and
01:27:09that can give a little bit more
01:27:11info about that and then other
01:27:13people are just saying thank you so
01:27:16thank you for thanking us an then.
01:27:18Oh yeah, there's more questions here.
01:27:23OK, for recurrent GM off study do you
01:27:27use Avastin alone or have you combined
01:27:31with lomustine or arena tecan? Yeah,
01:27:34so I think most of us based on some.
01:27:38Unperfect studies.
01:27:41That should be taken so that
01:27:44is no longer used in gems.
01:27:46Elect activity as a single agent and
01:27:49also in studies with Avastin, Lomustine.
01:27:52The jury is still out.
01:27:54I do offer that for pieces that
01:27:57can tolerate that and they have
01:28:00empty empty metalation.
01:28:02Specially if they responded
01:28:04well to alkylating agents,
01:28:05it's a potentially helpful,
01:28:08but there are no randomized
01:28:11trials to prove that.
01:28:12I really individualize
01:28:14it for a patient in my practice.
01:28:17On their performance
01:28:19status molecular factors.
01:28:21So doctor will turn.
01:28:22I would like to add for outside
01:28:25opinions with the kovid pandemic.
01:28:27Telemedicine is expanded and
01:28:28we offer Tele medicine to
01:28:29patients throughout Connecticut.
01:28:31Tele Medicine Licensure
01:28:32still is a state by state.
01:28:34There is some movement on the federal
01:28:36level to get more reciprocity
01:28:37so we can do more telemedicine
01:28:39consoles in different states,
01:28:41but that is something that
01:28:42we can take advantage of.
01:28:44An ideal has a good platform
01:28:46for Tele Medicine.
01:28:48And even during pandemic we have
01:28:51been transferring patients from
01:28:52from outside who want to seek the
01:28:55best care possible here. So yeah.
01:28:58Just because we were talking about
01:29:01avast and I think just why is Avastin
01:29:04called the last resort drug and is
01:29:06that an accurate description an there
01:29:09was another patient who also described
01:29:11that he has a G BM and did standard of
01:29:15care etc is now currently on Avastin.
01:29:18So why is Avastin used later and do you
01:29:22consider it to be a last resort drug?
01:29:27So I don't think the last
01:29:29resort is a good term here.
01:29:31I think it is.
01:29:34A very helpful drug.
01:29:36It's just about timing to use the drug.
01:29:40Needs to be individualized.
01:29:43Avastin is excellent too.
01:29:45Rapidly shrink tumors and
01:29:48decrease the per tumor edema.
01:29:52Which means that the patients
01:29:54can improve very quickly.
01:29:56And for those patients that have
01:29:59really bad neurologic symptoms.
01:30:01That is the time to use a faster.
01:30:04And
01:30:04I know you guys have oftentimes
01:30:07used it even early on,
01:30:09for you know really large tumor burdens.
01:30:11Multifocal disease where I,
01:30:13you know, in limited with what
01:30:15I can do with a, you know,
01:30:18extensive bihemispheric disease,
01:30:19that kind of thing.
01:30:22Correct, and that's a great point.
01:30:24We use it when needed.
01:30:25It can be used up front.
01:30:27Sometimes the patients are in the hospital.
01:30:30How they're going to get out of
01:30:32the hospital if they have a large
01:30:34tumor that can't talk the catwalk.
01:30:36So these are patients that
01:30:38really need Avastin up front.
01:30:40And I think the why there is so much
01:30:43concerns about the use of Avastin.
01:30:46This becausw we sort of lose the parameter
01:30:49of what's happening to the tumor.
01:30:52So avast and sort of cleans everything.
01:30:56And we do know that these tumors can
01:30:58sometimes continue to progress with no,
01:31:00we're not seeing you're not feeling it,
01:31:03but it sure could be progressing.
01:31:05And changing treatment would be in the order,
01:31:08but it's just if we can't identify
01:31:10when the change of treatment is and
01:31:13for that reason these patients are
01:31:15typically excluded from clinical trials.
01:31:17So that is the only downside,
01:31:19or Dustin,
01:31:20but I think for those patients
01:31:22that require vastly would not be
01:31:24candidates for clinical trials anyways.
01:31:25Be 'cause they were not feeling well.
01:31:28They were not doing well and they
01:31:30couldn't handle a clinical trial.
01:31:32So if Avastin is initiated because
01:31:34it was needed,
01:31:35and I think there is nothing
01:31:37wrong about that,
01:31:38and I think it is a good drug and I
01:31:40think it is vilified a little bit,
01:31:43but we now know how to use and
01:31:46when to use it.
01:31:49That a vest and is not very effective
01:31:51for the infiltrating tumor cells of GB,
01:31:54M and So what you may see is that a patient,
01:31:58after starting a vast,
01:31:59then after some months, will have
01:32:01worsening of neurological disabilities.
01:32:03And that's due to the infiltrative tumor
01:32:05cells spreading throughout the brain,
01:32:07which, unfortunately can be
01:32:08resistant to all chemotherapies.
01:32:10Something that we're still working
01:32:12hard on to improve treatments
01:32:14for, but it seems they liked your
01:32:17responses and then the final question,
01:32:20are you using optune novocure up
01:32:22front for most patients with GBS or
01:32:25do you use it in select patients?
01:32:30Well, I think Doctor Moreau made
01:32:32an excellent point that Optune
01:32:35is cumbersome to use divisible.
01:32:37Evidence that you have malignant brain tumor.
01:32:42So it's up to a patient.
01:32:44You know it's something that they do.
01:32:46And as as a Neural Oncologist,
01:32:48it's after you prove treatment that I
01:32:50make patients aware of offered to them.
01:32:52Tell them the data and then
01:32:53it's up to a patient.
01:32:55Some patients are able to embrace
01:32:56up to use it effectively,
01:32:58and then others.
01:32:59It would be challenging for them,
01:33:01and it's not something that
01:33:02they think is worth it,
01:33:04and the respect of persons decision,
01:33:05no matter which they choose and help them.
01:33:08You know,
01:33:08try to have the best treatment and
01:33:10outcomes that they could have.
01:33:14Yeah, well, I had a patient that was an
01:33:16engineer living in the middle of the Woods.
01:33:19We was very averse to people and he loved it.
01:33:22He were his device and he was an engineer.
01:33:24He thought he was a really cool
01:33:26thing and did not bother him at all.
01:33:29So for that kind of patient, sure.
01:33:31And then I have my Manhattan patients that
01:33:34would never actually wear that because
01:33:37they would never want to go to work even
01:33:41if they want to be seen wearing that.
01:33:43And for those patients,
01:33:45it was more important their appearance in
01:33:47their college life than the downsides of
01:33:50the potential benefits from opportunity.
01:33:52I think in the end it's again what
01:33:55we're all saying is, you know,
01:33:57a lot of these decisions are made
01:33:59in conjunction with the patients,
01:34:01and being informed is the
01:34:03most important thing.
01:34:04And being surrounded by expert
01:34:05opinions and experts in the field who
01:34:08can really give you all the options
01:34:10is really the most important thing.
01:34:12And we here are always available
01:34:14to answer any of those questions
01:34:16or give consultations as well.
01:34:17So and I also see Chris Cossano
01:34:19who's the president of Connecticut
01:34:21Brain Tumor Alliance.
01:34:22He thanked us as well and we thank
01:34:25him for his continued support of.
01:34:27Our patients in the Connecticut
01:34:29brain tumor lines.
01:34:30It's a great organization for
01:34:32patients with brain tumors.
01:34:33So in conclusion of did you say
01:34:35vitamin C should not be taken while
01:34:38undergoing chemo or radiation?
01:34:39Yeah, we usually tell you to stop.
01:34:43I tell you to continue it after surgery.
01:34:47It kills me to say that,
01:34:49but yeah, don't take it.
01:34:51Supposedly that's what they said,
01:34:53but in any event,
01:34:54thank you all for being here.
01:34:56It's past 7:30.
01:34:57We so appreciate you being here
01:34:59and spending your evening with us.
01:35:01We hope to do this again in the
01:35:04future for the providers that are on.
01:35:06We even hope to do really kind
01:35:08of like a mock tumor board so
01:35:10you can bring your cases here
01:35:13and we can help provide answers
01:35:15or even to patients we can help.
01:35:17Offer our opinions and such so will
01:35:20look forward to that in the future
01:35:22and please just reach out and contact
01:35:25us if we could be of any help.
01:35:27And to my Co mark my coat speakers.
01:35:30Thank you so much.
01:35:33Have a
01:35:33good night. Have a good
01:35:36night everyone be well.