Metabolic Imaging Techniques Using PET and MR Spectroscopy in Brain Tumors

April 11, 2022

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00:00Our next speaker will take neuroimaging
00:03in a completely different direction.
00:06Doctor Zachary Corbin,
00:08assistant professor of neurology,
00:09head of the Neuron Oncology
00:11Fellowship program.
00:11We'll be talking about neuroimaging
00:13and cancer. Thanks come on up.
00:27So thank you very much.
00:28It's really an honor and a
00:29privilege to be here. I'm Zach Corbin.
00:31I'm one of the neuro oncologist at Smilo,
00:33and I'm here to talk about metabolic
00:35imaging techniques using PET and
00:37Mr spectroscopy and brain tumors.
00:38I'd like to start by talking about.
00:40I can start by talking about the disease.
00:44We've directed a lot of our
00:46techniques to which is glioma and
00:48glioma is surprisingly common.
00:49I think to most people it's second most
00:52common type of primary brain tumor.
00:54US annual instance is 19,000 /.
00:5712,000 of these are the most aggressive
01:00and probably most famous glioma which
01:02is glioblastoma and despite a great
01:05deal of research and clinical efforts,
01:07it's a very morbid and mortal.
01:09Disease where over just over one
01:11in 20 patients at five years,
01:13remains alive, about 6.8%.
01:15At last measurement we'll blastoma is
01:18defined histopathologically with necrosis,
01:21which is also surrounded by
01:23pseudo Palisades here,
01:24and there's lots of nuclear changes,
01:26and you can see the cells look quite
01:27different on this microscope slide,
01:29and these are blood vessels.
01:30There's blood vessel proliferation.
01:32We're interested in applying metabolic
01:34imaging to the treatment of wheel
01:35blastoma and glioma in general because
01:37the glioblastoma, for example,
01:39is treated with a basis of MRI.
01:42MRI is a diagnosis.
01:43Patients are treated with surgery
01:45and then an MRI is performed again,
01:47postoperatively and then often within a
01:49month prior to the first phase of treatment,
01:51which is chemoradiation.
01:53Another MRI is performed and then
01:55actually after chemo radiation,
01:57which lasts about 1 1/2 months.
01:59One month of break.
02:00There's another MRI and we actually.
02:02Perform MRI's every two months
02:04during the adjuvant chemoradiation
02:06phase or sorry chemotherapy phase.
02:08So the average patient often receives
02:10about a dozen MRI's and this is a
02:13great opportunity for us to add to
02:15the patients care in order to tell
02:17you a little bit about why we would
02:19use metabolic imaging and glioma.
02:20So the Warburg effect is the most
02:23famous metabolic change and it's
02:24associated with aggressive tumors
02:26and in order to demonstrate it I'm
02:27going to show you a diagram where
02:29this is the outside of the cell.
02:31This is the inside of the cell.
02:32So glucose comes into the cell,
02:34it becomes pyruvate,
02:35and then there's a dichotomy
02:37where in general,
02:38in normal oxygen tension and
02:40through oxidative phosphorylation
02:41as mediated through.
02:43This is my mitochondria cartoon.
02:45You can see that CO2 evolves and is
02:48exchanged with bicarbonate and cytosol,
02:50alternatively usually in low oxygenation
02:53you'd have glycolysis performed,
02:55which involves lactate,
02:56which is acidic,
02:57and Warburg effect dictates that in
02:59the presence of normal oxygen tension,
03:02actually the right side of this diagram.
03:04Is favored,
03:04and actually tumors prefer to
03:06produce the lack produce lactate
03:08through the Warburg effect.
03:10So what I'm describing today are
03:12clinically available techniques to
03:14actually measure the Warburg effect.
03:16So Pat has been used in his famous
03:19as reviewed by Doctor Constable
03:21for many different radio ligands,
03:23fluorodeoxyglucose or FDG PET is
03:25the most common clinical tool.
03:27And with FDG pet, when we provided
03:30in the bloodstream of the patient
03:33it is phosphorylated into FDG.
03:35Inside the cell, but doesn't actually
03:37further used by the cell and really
03:39represents total glucose metabolism,
03:41but total glucose metabolism in this context
03:43is a rough characterization of oxidative
03:46phosphorylation without the specificity,
03:48so the specificity in our technique comes
03:50from another clinically available tool,
03:52which is Mr Spectroscopy,
03:54NMR spectroscopy, and in this case,
03:56emerse, spectroscopy.
03:57NMR, spectroscopic imaging using proton
03:59based methods can highlight lactate as
04:02well as other other molecules in the cell.
04:04And as a representative of mythologist.
04:06So as a part of my wife CIO award,
04:09we actually developed a technique in which
04:11we have labeled it the Warburg index.
04:13This is actually created at Yale
04:15and we actually are using lactate
04:17measured by Mr spectroscopy over SUV,
04:20which is standard uptake value
04:21measured by PET,
04:23to show the Warburg index and
04:25the Warburg Index works.
04:26So this is one of my patients in
04:28this protocol who has a glioblastoma
04:29and this is the tumor here.
04:31As you can see,
04:32causes changes to the brain,
04:34but I think that the Warburg.
04:35Index actually really does an
04:37amazing job of highlighting the
04:38metabolic derangement that was
04:39actually occurring in this tumor.
04:41So you can see blue is relatively normal
04:43metabolism of the surrounding brain,
04:45and the red indicates a high Warburg effect
04:48or high High warberg index in this case.
04:51In order to talk a little bit about
04:52why this might teach us about Juliana,
04:54though,
04:54I'm going to introduce another thing which
04:56is called the ISIS history dehydrogenase
04:58mutation, otherwise known as I.
04:59DHIDH is used and known in other tumors,
05:02but in glioma family it is.
05:04It defines a characteristic,
05:06and it really begins as discussing
05:08what IH does in the standard cell.
05:10So I H and the standard cell changes
05:13isocitrate to alphabetically rate,
05:15and that is actually a mediator
05:17in normal metabolism.
05:18But in an IDH mutant,
05:20there's a heterodimer.
05:21Formed, which produces what's
05:22called an ankle metabolite.
05:24That accountability is
05:25named 2 hydroxy glutarate.
05:27That's not as important to remember
05:29that this causes downstream changes,
05:30either directly or otherwise in
05:32methylation of the genome methylation
05:35of histones and actually patients
05:36do better who have these tumors.
05:39The tumors grow less,
05:40So what we are proposing is
05:42that the Warburg effect,
05:43which otherwise as I showed you
05:45might be very active in an ID
05:47file type tumor in an IDH mutant
05:49paradigm actually is shifted.
05:51Towards normal metabolism and
05:53oxidative phosphorylation,
05:54and is another mediator of
05:56better outcomes in these cases,
05:57and we have designed a study as
06:00part of my CI project where we
06:02have a prospective excuse me.
06:04Observational cohort 2 cohorts
06:06where both patients recruited both
06:08groups of patients recruited at
06:10Yale have a diagnosis of glioma.
06:12One group of patients has known ID
06:14H mutant glioma and one group of
06:17patients has known DH well type,
06:18so we'll perform for these patients.
06:20Brain MRI will measure the lactate.
06:22As I mentioned, we also can measure 2 hydroxy
06:25glutarate with protomer spectroscopy.
06:27We'll measure FDG pet. We'll perform
06:29whole genome methylation studies,
06:30and we'll measure clinical outcomes in
06:33radiography or conventional pathophysiologic
06:36outcomes through standard scanning.
06:38So I've had the privilege of actually
06:40scanning several patients now,
06:41and I can show you the way that
06:43this actually seems to work.
06:44So I H. Mutant tumor here is seen
06:46as seen in generally appears quite
06:49similar on a standard MRI.
06:51This is actually also a high grade glioma,
06:54but a main difference.
06:55This is an oligodendroglioma
06:56that's and otherwise.
06:57Characterizes anaplastic or Grade 3
06:59and so an IH mutation is present in
07:01this tumor and you can see that it
07:04actually looks quite different with the
07:06Warburg index and so this is a tumor
07:08that a seasoned neuro oncologist would
07:10know is going to behave differently.
07:11And I think that actually the metabolic
07:13image really underscores the behavior.
07:15These patients clearly do much better
07:17than patients who have glioblastomas
07:19and so another method that we've
07:20been working on which was also
07:21introduced by Doctor Constable,
07:23is deuterium metabolic imaging,
07:24and this is a through my collaborators.
07:26We use something called.
07:28Stable isotope method.
07:28So we actually give someone
07:30they just drink it,
07:31they just drink deuterated glucose
07:32and you can actually watch
07:34the tutorial and the scanner.
07:35You can watch it go through this whole
07:37paradigm that I laid out for you.
07:39It's a slight difference in that we
07:40measure glutamate and glutamine as a
07:42measure of oxidative phosphorylation,
07:44and we can't differentiate the two and
07:45you'll see it referred to as a GLX,
07:47but that's the measure of oxidative
07:49phosphorylation and to detect
07:50the Warburg effect in this case,
07:51we once again actually have direct
07:53measures of bicyclists and oxidative
07:56phosphorylation.
07:56This is the technique that was
07:58also developed.
07:59At Gill and I'm excited to show
08:01you some more data from HDMI so
08:04the Warburg effect is seen.
08:06Here we saw before as well.
08:08This is another patient.
08:09This is my patient who had glioblastoma
08:11and you can see lactate is far
08:13exceeding glutamate and glutamine
08:15and really highlights the metabolic
08:16activity of the tumor and we actually
08:19have been able to image multiple
08:21patients with glioblastomas at
08:22different times in their treatment.
08:24So this is a patient.
08:25Also a separate patient who has
08:28an asthma at diagnosis.
08:29And I mentioned that the first
08:31stage of treatment the patients have
08:32radiation with chemotherapy and we
08:34actually weren't able to detect
08:35the Warburg effect in this case.
08:36And then you can see two instances
08:38where we were able to scan patients
08:40who had recurrent disease and we were
08:42able to detect Warburg effects that
08:44actually appear slightly different.
08:46So this this tells us that these
08:48techniques might,
08:49in addition to telling us something
08:51about diagnosis and maybe even prognosis.
08:53They may tell us about treatment
08:55of of the tumors.
08:56So I think future directions for
08:58metabolic imaging and neurology
09:00at Yale are rich and exciting.
09:02The Warburg index, the technique I
09:04told you about using MRI and PET.
09:06We're hoping to complete the
09:07recruitment of both cohorts.
09:09We're looking forward to
09:10measuring these genetic radio,
09:11graphic and clinical links.
09:12This is a clinically available,
09:14rapidly scalable test that
09:15was developed at Yale.
09:16I think this is exactly the type
09:18of tool that Y CI is featuring,
09:20and we're hoping to deploy
09:22this into clinical trials in
09:23the future and then determine
09:25metabolic imaging is also a Gale.
09:26Your own technique,
09:27which we are also actually
09:29currently trying to
09:30deploy to clinical trials,
09:31and also we're looking forward to
09:33deploying this on our clinical scanners.
09:35Perhaps first at Yale, New Haven Hospital.
09:38I think that these will tell us
09:39as always mentioning diagnosis,
09:41prognosis but also measures of
09:42treatment effect in the future.
09:44And so I want to thank everyone
09:46who's helped me get this far.
09:48This is my lab, my postgraduate,
09:50the alumni of my lab.
09:52Of course the YC Scholar Award
09:54and the privilege to be here and
09:56also my collaborators are O.
09:57One for deterring metabolic
09:58energy and I want to I would be
10:01remiss to not thank everyone,
10:02but especially the teams.
10:04Actually my first TL one award was
10:06with the Stanford spectrum with Doctor.
10:08Steinberg, but in addition,
10:10my my mentor doctor Rect
10:12Stanford doctors hafler amoro,
10:15bearing Blonden and Kim and our
10:17fellow Mary Barton at Yale Neurology,
10:20doctors Channel and Moliterno.
10:21Yale neurosurgery.
10:22Of course, the YCI,
10:24including Doctor Shapiro Cantley and
10:26Sinha of course MRC that's my buzzer.
10:29I'm overtime, but I'm almost done,
10:32doctors, Rothman, doctors, Degraff,
10:34Dr, Defeater, and then of course,
10:36at the Yellow Pet Center.
10:37Doctors Carson.
10:38And Chen and the last,
10:40but definitely not least,
10:41doctors,
10:41Contessa and Bindra with Yale
10:42Radiation Oncology.
10:43So thank you guys very much for your time.