Brain Tumors and Stem Cells

Part 1: Brain Tumors

00:00:00.22 Hello. My name is Alfredo Quinones-Hinojosa.
00:00:03.21 I'm an associate professor of Neurosurgery, Oncology, Cellular and Molecular Medicine,
00:00:09.15 and Neuroscience at Johns Hopkins University Medical School.
00:00:12.23 I am delighted and honored to talk to you about brain tumors today.
00:00:16.23 I will be talking to you about the history of brain tumors,
00:00:19.29 types of brain tumors that one may encounter when dealing with this disease,
00:00:24.19 a treatment, mainly of the non-cancer brain tumors
00:00:29.27 with a special focus on the cancer brain tumors,
00:00:32.17 the possible etiology of some of these tumors,
00:00:36.09 as well as the future research that my group, as well as other groups around the world,
00:00:41.16 are conducting on this disease.
00:00:43.14 Let me take you through the history of brain surgery.
00:00:48.05 It turns out that it was not too long ago -- a little bit over a hundred years ago --
00:00:52.22 brain surgery was an unexplored frontier.
00:00:55.16 At Johns Hopkins University, a young surgeon, by the name of Harvey Cushing
00:01:00.01 was one of the pioneers of not only understanding the brain
00:01:05.18 from the inside by doing brain surgery,
00:01:09.08 but also developing new techniques to be able to do things that now,
00:01:15.17 at present times, we take for granted.
00:01:18.02 This was the image of one of his own illustrations
00:01:23.03 that he did, as he was coming out of the operating room.
00:01:26.16 And as you can see, he was mapping all the way from the leg, the arm, the neck,
00:01:31.02 the face, the head, the tongue, eyes, speech,
00:01:34.23 eye, hearing, here at the bottom, and vision in this area.
00:01:39.19 An incredible amount of work that it took for him to do this in 1903,
00:01:46.12 at the Johns Hopkins Hospital.
00:01:48.05 This was the beginning of brain surgery.
00:01:50.27 By the 1930s, Dr. Penfield, out of Canada, who was also a disciple of Harvey Cushing,
00:01:56.28 was able to produce the so-called homunculus,
00:02:00.22 which is what we now learn during our education.
00:02:05.04 This is the overall mapping of the cortex of the brain.
00:02:09.20 This is what allows us to sometimes find corridors
00:02:15.28 and ways to go into the brain without hurting the normal function of the brain.
00:02:23.27 It was thanks to these pioneers early on that we are now able
00:02:28.22 to take on some of the most challenging brain cancers
00:02:31.28 and brain tumors that are known to humans.
00:02:35.09 This is the picture of an extra-axial tumor. That means not from the brain.
00:02:41.27 Some people may even call these tumors benign
00:02:45.10 in nature. Why? Because they're not truly
00:02:48.03 invading the brain. But, I would dare someone,
00:02:50.28 and I would challenge anybody to call this gigantic tumor benign.
00:02:56.01 It doesn't matter if it doesn't penetrate the brain.
00:02:59.11 Just the fact that this tumor is so large
00:03:03.10 and is putting so much pressure on normal parts of the brain
00:03:07.14 that makes the surgery challenging.
00:03:10.11 Yet, we can still achieve cures in some of these tumors,
00:03:16.23 if they are the non-cancerous type.
00:03:20.09 This is an illustration, as you can actually see right here
00:03:23.14 seen from the top of such a tumor.
00:03:27.14 This is a so-called focal tentorial meningioma.
00:03:32.09 Giant in nature.
00:03:33.22 And as you can see, we have to take into account
00:03:36.20 not only the anatomy of the tumor,
00:03:40.08 which is seen right here, but also the anatomy
00:03:43.22 of some of the blood vessels that are extremely crucial
00:03:47.15 for us to preserve and not injure the patient.
00:03:52.00 Some of these procedures are challenging.
00:03:55.01 Some of them can go on for 20-24 hours, multiple teams working together.
00:04:01.05 Yet, some of these challenging tumors, if they are the non-cancerous type,
00:04:06.15 they can still be cured with surgery.
00:04:10.28 Especially at centers that specialize with a large volume of cases
00:04:15.06 on the treatment of this disease.
00:04:17.05 This is the post-operative scan of this particular patient
00:04:21.04 that I did with some of my colleagues a number of years ago.
00:04:24.04 And, as you can see, we were able to successfully remove
00:04:27.21 this gigantic tumor that was in the back of the head
00:04:32.25 of this patient that was having severe symptoms.
00:04:36.23 I'd like to illustrate to you one particular case presentation.
00:04:42.04 This is a young woman that I saw a couple of years ago.
00:04:46.24 A 38-year old previously healthy woman
00:04:51.00 presented to the emergency department with severe headaches.
00:04:55.13 She was also experiencing diminished smell and taste over the course of the last year.
00:05:02.20 Her personality, as you can see, was of a flat affect
00:05:07.24 and decreased smell.
00:05:10.08 So, she was clearly having some symptoms
00:05:13.05 from what was found to be a very large brain tumor
00:05:18.07 in the anterior cranial fascia.
00:05:20.19 As soon as I saw those images, at that time,
00:05:24.24 I imagined that this was going to be a challenging procedure.
00:05:28.10 I thought, in my differential diagnosis that this lesion was going to be a tumor
00:05:37.06 that did not come from the brain.
00:05:40.03 The so-called extra-axial tumor.
00:05:42.25 And, at the top of my differential was a meningioma,
00:05:46.07 based, not only on the MRIs, which you can actually see in the axial cut...
00:05:51.24 These are cuts that are going like this through the brain.
00:05:54.12 You can actually see the anterior cranial fascia.
00:05:58.09 These are multiple different cuts. In this corner right here,
00:06:01.26 you can actually have a little bit of the idea
00:06:04.22 of the eye sockets, so we're cutting right above the eye sockets.
00:06:09.04 And then we come below, right here,
00:06:11.15 and you can see all this white stuff.
00:06:14.18 That's all the swelling in the brain.
00:06:16.28 So, this tumor is giant in nature,
00:06:19.14 and it's putting so much pressure on the brain
00:06:21.21 that the brain is swollen.
00:06:23.26 So, I had the idea that this was going to be a non-cancerous tumor,
00:06:28.09 but one that was going to be challenging to take out.
00:06:31.18 So, we took this patient to the operating room.
00:06:33.29 We did an incision from ear to ear, because the tumor was quite challenging.
00:06:37.25 We pulled the skin forward, as you can actually see in this illustration right here.
00:06:42.07 We took out the bone that's the frontal bone --
00:06:45.22 this portion of the bone, which is this right here --
00:06:48.19 then we took out the bone right above the eyes --
00:06:52.27 This rim of bone right here -- in order for us to be able to come straight down
00:06:59.25 into this region, into the brain without putting
00:07:04.15 any retraction on the brain whatsoever.
00:07:08.10 And this is a picture, an illustration just like you're seeing me right here.
00:07:12.08 The skin is pulled forward, we're coming right at the base of the skull
00:07:17.14 in order to minimize the retraction of the brain.
00:07:21.16 Ideally, you want to put no retraction of the brain whatsoever
00:07:24.28 because you want to preserve as much function of the brain as possible.
00:07:28.09 So, this tumor was coming right here.
00:07:31.12 My suspicion, once again, is that this was a non-cancerous tumor
00:07:35.24 that we could potentially achieve a cure on this patient.
00:07:40.10 So, we ended up taking the patient to the operating room,
00:07:43.18 and you remember this gigantic tumor in the anterior cranial fascia,
00:07:47.17 and it's completely gone and cured.
00:07:51.09 We were able to achieve a cure on this patient.
00:07:54.19 Years later, we have followed her, and her personality has come back to normal.
00:07:59.11 Olfaction, unfortunately, was gone because all the olfactory nerves
00:08:04.23 that were in this area were invaded by this tumor
00:08:09.20 that was not cancerous in nature, but nonetheless,
00:08:12.10 they were so thin and so damaged that there was no possible way to dissect them away.
00:08:16.23 So, we were able to achieve a cure
00:08:19.25 on this tumor, and the final pathology
00:08:22.06 ended up being a meningioma.
00:08:24.09 Let me show you another tumor that is thought to be non-cancerous in nature.
00:08:28.28 This is what we call a pituitary giant adenoma.
00:08:33.25 Pituitary adenomas are not thought to be cancers because they don't invade the brain,
00:08:39.07 but I would also dare anybody to tell me that this is not a dangerous tumor.
00:08:44.07 You can see, it's almost the size of a tennis ball
00:08:48.00 that has grown right at the base of the skull, up into the brain,
00:08:51.26 and it's putting a fair amount of pressure. Up here is the corpus collosum.
00:08:57.01 You can actually see the vessels completely pushed upwards
00:09:01.07 in this area. You can actually see right here,
00:09:03.29 on the bottom, the brain completely pushed laterally like this.
00:09:09.11 A very, very challenging tumor to take out.
00:09:14.15 We have, at our institution at Johns Hopkins and other parts of the world,
00:09:18.28 people have tried to do this surgery.
00:09:22.20 Surgery for brain tumors that are not cancer is much more minimally invasive.
00:09:28.24 At our institution, we have devised ways
00:09:32.27 to be able to take these tumors, sometimes, depending on the size, even through the eye
00:09:39.20 This is a picture of an eyebrow, and you can actually see the eye
00:09:43.27 right here where we took the tumor... some tumors
00:09:47.16 through this approach right here.
00:09:49.02 This is a view, as we're going right through the brain, right here,
00:09:53.06 moving the brain away, getting right under the skull,
00:09:56.26 because the challenge is obviously to get right under the brain,
00:10:01.20 get into that area, and extract these tumors.
00:10:03.23 Another way of taking these tumors out
00:10:06.29 is by doing it transphenoidally.
00:10:09.06 This is a picture of a young child. We have actually developed some of these techniques
00:10:14.00 and perfected some of these techniques at our own institution
00:10:17.04 Going through one nostril, as you can see right here,
00:10:19.28 to be able to take this tumor out
00:10:23.26 right here using maneuvers in the operating room.
00:10:28.05 Sometimes using the own fat of the patient
00:10:31.14 to be able to reconstruct the base of the brain,
00:10:35.13 as you can see right here,
00:10:37.16 and to be able to achieve a cure in these non-cancerous tumors.
00:10:42.21 So, once again, we can achieve a cure
00:10:45.18 in tumors that are not cancerous, not all the time, but the majority of the time
00:10:49.25 if we do the appropriate approach, the appropriate surgery
00:10:53.19 and if a multidisciplinary team is involved.
00:10:57.28 Some of these tumors require a combination between a brain surgeon
00:11:01.13 and an ENT surgeon, or a plastic surgeon,
00:11:04.02 depending on the approach. I always encourage my patients
00:11:07.23 to not only seek a second opinion and go to major tertiary care centers
00:11:12.27 that specialize and do a large volume of these procedures
00:11:16.13 because I think it's very important to have a good understanding
00:11:20.17 of anatomy and plenty of experience in doing these approaches.
00:11:24.01 But what about those tumors
00:11:26.13 that are considered to be cancerous?
00:11:29.17 One type of tumor that is increasingly being more heard about
00:11:35.18 in the media because of people like Senator Kennedy
00:11:40.04 that was afflicted by a glial tumor
00:11:42.19 also known as a glioblastoma.
00:11:44.25 These are the so-called intraaxial tumors.
00:11:48.16 We have, within the intraaxial tumors,
00:11:51.08 we have the low-grade gliomas, we have the high-grade gliomas.
00:11:56.11 Within the low-grade gliomas, we have the juvenile pilocytic astrocytomas --
00:12:03.22 the so-called JPAs -- we have the astrocytomas, and the oligodendrogliomas.
00:12:09.26 They're all in the family of cancers.
00:12:12.17 But the low-grades tend to have a much better prognosis than the high-grades.
00:12:17.16 That is, those patients that have a low-grade glioma
00:12:21.04 tend to survive much longer
00:12:23.24 versus those patients that have a high-grade glioma.
00:12:27.11 The most devastating being the glioblastoma multiforme.
00:12:30.22 Now, I'll tell you something. I believe that glioblastoma multiforme
00:12:35.17 is the most devastating cancer that affects the most
00:12:40.20 beautiful organ in the body, which is the brain.
00:12:45.21 One of the challenges that we face is that by the time that these tumors get diagnosed,
00:12:49.23 specifically the glioblastoma multiforme, the GBM,
00:12:53.21 most of the cells that we can take out with surgery
00:12:58.06 are visible in MRIs and sometimes they're visible in surgery.
00:13:04.06 So, we can achieve a very good resection of these tumors
00:13:09.07 where we can see. The problem is that as we look back in history,
00:13:13.02 a lot of the cells that are malignant
00:13:16.28 have already migrated away from the brain,
00:13:20.17 and if you look at some of the studies that have been done
00:13:23.12 up into the contralateral side of the brain,
00:13:26.17 one can actually find cells that have already migrated, and that's one of the reasons
00:13:33.13 why we can't achieve a cure with brain surgery for this cancer.
00:13:38.05 And this is an important distinction to make between those tumors
00:13:41.19 that some people may call benign
00:13:43.22 like the meningiomas or the pituitary adenomas
00:13:46.06 versus these tumors that are considered to be malignant
00:13:49.07 and invasive. This is true cancer. Cells have actually moved away from this region.
00:13:54.12 This is a picture of the necessity
00:13:59.28 that one has to be able to help patients
00:14:05.04 and sometimes to achieve the best possible resection during surgery.
00:14:11.03 This is a patient that had the tumor before and after
00:14:15.24 and underwent a sub-total resection.
00:14:19.05 This is a tumor. They had a tumor before and after
00:14:24.02 and had a near total-resection.
00:14:27.11 This is a patient that had a tumor before and after and achieved a gross total resection
00:14:35.11 in a low-grade astrocytoma.
00:14:40.07 Once again, it's still in the family of cancer, but this is the low-grade type.
00:14:43.23 When we look at the overall survival of these patients...
00:14:48.10 This is a Kaplan-Meier. In this axis we have the percent survival,
00:14:53.11 and this axis, we have the months.
00:14:55.17 Then, you have gross-total resection (GTR) as seen right here.
00:15:00.22 Then you have near-total resection (NTR), and then you have sub-total resection (STR).
00:15:08.28 So, it's clear that the more tumor we can take out in our patients,
00:15:13.29 the better those patients will do after surgery.
00:15:17.22 And that is an important distinction to make. That's why these patients need to
00:15:22.13 be seen, in my opinion, by people that have a fair amount of experience
00:15:26.10 taking these tumors out.
00:15:27.21 What about the perspective on the glioblastoma multiforme?
00:15:32.00 I told you already, within the brain tumors, it's a spectrum.
00:15:35.11 The low-grades to the high-grades.
00:15:39.04 The low-grades being tumors like the oligodendroglioma
00:15:42.11 the astrocytoma, juvenile pilocytic, or the low-grade astrocytoma,
00:15:47.26 versus those tumors that are high-grade
00:15:49.29 like the anaplastic astrocytoma or the most devastating,
00:15:54.17 the glioblastoma multiforme.
00:15:56.12 In 1978, the median survival for these patients
00:16:00.20 was about 10 months. That means many patients survived less than 10 months,
00:16:06.26 and some patients survived more than 10 months.
00:16:10.19 By 1990 and the 2000s, most people began to do much more
00:16:17.08 aggressive not-only resection, but to treat these patients
00:16:20.13 with chemotherapy and radiation,
00:16:22.12 and Roger Stupp in the New England Journal of Medicine published this paper
00:16:26.02 after gross and the best surgical resection that one can do,
00:16:32.04 followed by radiation and chemotherapy,
00:16:34.08 the median survival went from about 10 months to 14.6 months.
00:16:39.13 Now, some of you guys may think that that's not a lot,
00:16:42.06 but it's about a 50% increment in the survival of these patients.
00:16:46.19 And this is something that one has to take into consideration,
00:16:49.17 if one day we are going to be able to make a difference.
00:16:54.22 We can't give up in this disease, which is the so-called glioblastoma multiforme.
00:16:59.06 This is an MRI of a patient that has a glioblastoma multiforme.
00:17:04.08 What you see right here is what I can possibly take out in the operating room.
00:17:09.26 Now, this is a tumor that is in the dominant hemisphere of this patient.
00:17:15.23 This is an axial cut and this is a coronal cut.
00:17:19.22 Now, we have been able to confuse many people
00:17:24.05 because we actually flip the images. In this case, this is the right side of the patient,
00:17:32.09 even though it may look to you like the left side,
00:17:34.06 and this is the left side of the patient.
00:17:36.24 Once again, this is the right side of the patient,
00:17:39.13 this is the left side of the patient.
00:17:41.20 The images are flipped.
00:17:43.24 In this case, the patient has a tumor in the dominant hemisphere.
00:17:48.02 And I will tell you a little bit as to how we best do this surgery.
00:17:53.01 Before the surgery, most of us use what is called a navigation system.
00:17:58.20 And the best way that I can explain this is that we take an image of your brain
00:18:03.14 before the surgery with very high definition magnetic resonance imaging (MRI).
00:18:09.23 And we bring those images into the operating room,
00:18:13.05 and we use something that is similar to a GPS that you use in your car.
00:18:18.19 So that means that when we're pointing into your brain
00:18:22.03 we have a better idea as to where you or I are in reference to a pathology.
00:18:30.15 I know where I am, and I use little pointers to make sure that I am in parts of the brain
00:18:36.20 where I'm going to be able to take these lesions out.
00:18:39.06 And, in this case, it might not be perfect.
00:18:43.20 But, it's one of the closest things that we have to be able to have a better idea
00:18:50.11 of how we are going to navigate.
00:18:52.27 It's not perfect because as you can imagine, once you open the brain,
00:18:56.18 things shift a little bit.
00:18:58.07 So now you're dealing with shift of the brain
00:19:01.06 and an image that was done before we had opened the brain.
00:19:04.23 Nonetheless, this is a very good start to be able to navigate the brain
00:19:09.13 and to achieve, ideally, a much better resection of these tumors.
00:19:14.10 What do these tumors look like?
00:19:16.13 So, I'm going to take you now into the operating room,
00:19:19.03 and I'll show you this surgery. This is a young patient
00:19:23.12 in which I am taking a tumor near the motor cortex.
00:19:27.13 I have been been able to map the arm in this area,
00:19:31.13 and the forearm, and this, as you can see, is the tumor
00:19:35.29 that we're taking out. I am working inside of the tumor
00:19:38.25 between a very large blood vessel --
00:19:41.19 a vein -- that I am trying to preserve.
00:19:44.21 And what I'm doing right here is using a small device that is called a bite puller
00:19:50.11 and a suction right here and I'm getting towards the edge
00:19:53.22 of the tumor, and I am making sure that I am resecting as much tumor
00:19:59.00 as possible without compromising
00:20:02.11 the normal function of this patient.
00:20:05.05 We are working on the right side of the brain,
00:20:08.11 in this case, so it's not the left side,
00:20:11.09 otherwise, sometimes we would have to do these patients awake
00:20:15.16 if the tumor was near the eloquence parts of the brain.
00:20:18.22 So, we're working on the right side of the brain.
00:20:20.22 I introduced a small piece of cotton ball to be able to just control the hemostasis
00:20:25.29 -- the blood -- sometimes I try not to use this device too much because
00:20:30.22 it actually coagulates the small blood vessels,
00:20:33.23 and right now I am getting under the vein right here
00:20:37.19 and as you can see, there's still a little bit of tumor left
00:20:41.02 right here. I'm towards the end of resecting this tumor.
00:20:45.12 This tumor ended up being an intermediate grade tumor,
00:20:49.23 and we gave the patient a gross total resection,
00:20:51.27 and this surgery took place over three years ago, and the patient has done very, very well.
00:20:57.21 So this is the resection. I have taken you into the operating room.
00:21:02.16 This is the post-operative image of the patient that I showed you
00:21:07.05 after doing a gross total resection of this tumor.
00:21:10.19 As you can imagine, these patients, if the surgery is properly done,
00:21:14.21 if we map this brain well, we can achieve very good resection,
00:21:18.23 and these patients can do very, very well.
00:21:20.18 This is an estimated Kaplan-Meier plot of survival
00:21:24.10 of patients with Grade III astrocytomas.
00:21:28.12 Remember, Grade I through Grade IV.
00:21:30.25 Grade I and Grade II are the low-grade gliomas.
00:21:34.18 Grade III and Grade IV are the high-grade gliomas.
00:21:38.08 And the Grade IV is the glioblastoma multiforme.
00:21:41.12 Here, you have gross total resection, near total resection, and sub-total resection.
00:21:46.08 Gross total and near total are significantly different than the sub-total resection.
00:21:52.16 This, as you can see, is the percent survival,
00:21:54.27 and these are the months that the patient survived.
00:21:57.25 The more tumor you can take out the better these patients will do.
00:22:02.28 And that is a very, very important difference.
00:22:05.29 Sometimes, you can achieve very good resection, if you not only understand the anatomy,
00:22:10.27 but if you also use the state of the art
00:22:13.00 technology, mapping techniques, and other technical adjuncts
00:22:19.14 that you can use in the operating room.
00:22:21.10 This is the role that extent of resection has in survival
00:22:26.13 after the resection of the malignant astrocytomas.
00:22:29.20 This is the Grade IV astrocytoma.
00:22:33.10 And this is after primary resection, and you can actually see gross total resection
00:22:37.25 as the top curve, then there is near total resection as the middle curve,
00:22:44.18 and then there is sub-total resection as the lower curve in this case.
00:22:49.26 This is the percent survival on this axis, and these are the months.
00:22:53.29 The more you can take out, also in this Grade IV,
00:22:57.12 the so-called glioblastoma multiforme,
00:22:59.21 the better those patients will do.
00:23:02.11 It's not only important, the first surgery, which is the primary resection
00:23:07.00 as you can actually see right here -- this is the first surgery.
00:23:10.00 But, what if you have to go a second time? The second surgery, called revision surgery,
00:23:14.28 is also important. Gross total resection, right here, again.
00:23:19.03 Percent survival on this axis, months on this axis.
00:23:22.26 And you can see that the more you can take out,
00:23:26.06 the better these patients will do. The more they survive.
00:23:31.07 So, the extent of resection is important, not only the first time of surgery,
00:23:35.07 but also the second time of surgery.
00:23:38.13 But what happens
00:23:41.15 if maximal surgical resection is the goal?
00:23:44.26 What is the effect on survival for patients with malignant gliomas
00:23:49.22 who acquire surgically-induced neurological deficits?
00:23:53.22 It makes no sense, if you can take everything out,
00:23:56.25 but if you leave the patient completely devastated and hemiplegic,
00:24:00.14 then it may actually work against you.
00:24:03.05 And we have looked, in our own work, and a lot of the data that I've shown you
00:24:07.28 is based on our own work at Johns Hopkins
00:24:10.14 that this is actually true.
00:24:12.18 This is the Kaplan-Meier, once again --
00:24:14.14 the association of surgically-acquired deficits and survival.
00:24:20.04 This is after primary resection of a glioblastoma multiforme.
00:24:24.14 In the black line, we have no new post-operative deficits.
00:24:31.27 In the blue line, as you can see right here, we have new post-operative motor deficits.
00:24:38.11 And in the red line, we have new post-operative language deficits right here.
00:24:44.17 This is the percent survival, and these are the months.
00:24:48.10 As you can see, there's a significant difference if you do a great surgery,
00:24:53.08 and you take everything you can, and after the MRI, you look at it,
00:24:58.10 you don't see anything that has contrast.
00:25:01.00 But, if you give the patient either a motor or a speech deficit,
00:25:06.14 those patients will survive less.
00:25:10.01 And their quality of life will be absolutely devastated.
00:25:15.05 This is why doing a good surgical planning, and
00:25:18.24 being at a major tertiary care center
00:25:21.08 for the resection of these tumors is, in my opinion, crucial.
00:25:24.01 I'll take you now into the intraoperative setup,
00:25:27.25 not only that I show you what the surgery looks like,
00:25:30.07 but let me take you in for you to see some of the pictures
00:25:33.00 and some of the issues that we deal with
00:25:35.10 in our planning of these surgeries.
00:25:37.13 You can actually see. This is the intraoperative setup for an awake
00:25:41.16 craniotomy. This is the left side of the brain right here.
00:25:44.28 An anesthesiologist is on this side right here,
00:25:47.07 and we're all working together with a very large number of people
00:25:51.05 in this very state of the art surgical room.
00:25:54.21 We have a stimulator right here to be able to stimulate the brain
00:25:58.24 when we are doing the surgery.
00:26:00.25 At the time of the surgery, sometimes these patients can be awake
00:26:04.18 or they can be asleep. The tumor can be in the dominant hemisphere.
00:26:07.18 That is the left side. Or they can be in the motor-sensory area
00:26:12.12 for those tumors we have to do motor and sensory mapping.
00:26:16.08 For patients that have a tumor in the left side of the brain,
00:26:19.10 many times we have to actually do awake craniotomies.
00:26:24.26 We go on and we put small electrodes on not only the arms and legs,
00:26:30.23 because sometimes all it takes is just a little twitch, and sometimes you just can see it,
00:26:35.12 but with these small electrodes that are recording EMGs
00:26:39.22 that is muscles that are twitching,
00:26:42.06 we can actually detect very subtle abnormalities.
00:26:45.19 We go on and stimulate.
00:26:47.22 This is what is called intraoperative localization of not only motor,
00:26:51.07 but we can also use this device and this is the little electrode right here,
00:26:55.19 which is no bigger than about 5 millimeters in distance --
00:26:58.18 between these two electrodes right here is about 5 millimeters.
00:27:01.27 We use this to stimulate if we want to map the motor portions of the brain
00:27:06.29 or if we want to map the speech centers of the brain,
00:27:10.16 we use such a stimulator.
00:27:12.13 This is a picture of what it looks like right here.
00:27:15.08 In this case, we were on... In the operating room, we
00:27:20.02 mapped the motor shoulder, the motor forearm,
00:27:24.00 the motor hand, motor hand right here,
00:27:27.21 and in this case, the sensory hand and arm.
00:27:32.00 And the lesion, roughly speaking is all this area right here.
00:27:37.11 And notice how this tumor has displaced... opened up the space
00:27:43.11 in this region, where these cortical, eloquent parts of the brain
00:27:48.15 are found. So, we have to be very careful.
00:27:51.07 Some of the modern technologies that we use have been published by other groups.
00:27:56.21 And we can actually use the so-called diffusion tensor imaging of
00:28:01.06 sub-cortical white matter tracts.
00:28:03.12 So, we get a sense as to the relationship between a tumor
00:28:07.23 and parts of the brain that are important for naming,
00:28:10.23 parts of the brain that are important for movement of the mouth,
00:28:14.28 parts of the brain that are important for producing speech,
00:28:18.08 and you can actually see such a picture, sideways like this,
00:28:22.01 of a tumor that is surrounded by all of these spinal tracts.
00:28:25.23 So, we have to pay close attention to this.
00:28:29.10 I'll take you back, into a surgery.
00:28:31.24 There's just a few hours before the surgery in which I mapped a brain
00:28:39.11 in the operating room, in which I am looking at all the spinal tracts
00:28:44.17 that carry a lot of information on the brain, and what I'm doing right now,
00:28:49.01 is mobilizing the brain, and looking at it from different angles right here.
00:28:54.15 I have recorded this. I'm looking from the back right here.
00:28:58.21 I am using my mouse and moving the tumor.
00:29:01.04 I want to get an idea of where the tumor is in reference
00:29:04.09 to all these cortical, spinal tracts. All these tracts that send information.
00:29:09.03 I'm looking at it from the bottom.
00:29:10.14 I'm looking at it from the top.
00:29:12.05 I'm looking at it from the side.
00:29:13.22 Every single possible angle, because I am picturing in my brain
00:29:19.04 in a 3-dimensional way, which way is going to be the way that is going to allow me to
00:29:26.04 go in to the brain and minimize the injury to those eloquent
00:29:31.22 white matter tracts that carry a lot of information from the brain
00:29:38.16 down to the brain stem.
00:29:39.17 So I'm actually doing this, and I spend sometimes hours,
00:29:43.19 sometimes days, studying these cases to make sure that, in the operating room,
00:29:49.09 I maximize the likelihood of minimizing injury to these patients.
00:29:54.09 As you can imagine, not only... Awake craniotomies are challenging
00:30:00.10 for the patient as well as for the surgeon.
00:30:03.22 Having a relationship with the patient, having a two-way conversation before the
00:30:10.16 surgery will maximize the likelihood that during surgery,
00:30:14.05 the surgeries will have a better result.
00:30:17.21 We usually use the speech mapping, once again,
00:30:20.25 for tumors that are in the left side of the brain.
00:30:23.19 We can look at Broca's Area, which is for production of speech,
00:30:28.17 which is that little area right here in the front.
00:30:30.19 We can look at understanding of the speech,
00:30:34.28 which is also known as Wernicke's Area, which is in the temporal portion of the brain.
00:30:39.19 And then we can look at the connection pathway between these two regions,
00:30:43.13 Broca's Area, Wernicke's Area, and the conduction pathway s
00:30:49.00 that connect Broca's to Wernicke's right here.
00:30:53.06 So, whenever we have a tumor in the left side of the brain --
00:30:57.01 that is, in this vicinity -- most of the time, I do recommend an awake craniotomy,
00:31:03.16 unless there's a contraindication to awake craniotomy.
00:31:06.24 Sometimes, I actually recommend that we do a functional MRI,
00:31:13.13 which is also known as fMRI to look at anomia, speech arrest,
00:31:18.17 yellow motor, and we have, as well as other groups,
00:31:22.15 done a correlation between the areas that the functional MRI gives you,
00:31:26.08 and the areas that we actually stimulate in the brain
00:31:29.20 with the Ojemann stimulator during surgery.
00:31:33.08 So, these studies have been done that these are reliable methods
00:31:36.16 to get a sense as to whether or not
00:31:39.16 we should do a patient asleep or awake.
00:31:43.12 In general, my preference is, when there is a tumor in the left side of the brain,
00:31:48.09 which is in this case. Remember! The image is flipped!
00:31:51.14 This is the left side of the brain. This is the right side of the brain.
00:31:54.17 So, in this case, most of these patients, I do recommend an awake craniotomy.
00:31:59.22 I do get asked that question -- when to do an awake craniotomy.
00:32:02.16 Most of the time it's for speech, sometimes, some patients also get awake craniotomies
00:32:07.24 for tumors that are near the motor and sensory area
00:32:11.18 to be able to map those areas very well.
00:32:14.11 And sometimes it becomes a surgeon's preference to do this.
00:32:18.25 This is the picture of one of my own patients, which I did
00:32:22.07 all the way back when I was a resident,
00:32:25.04 the mapping of several languages. We now know that patients can actually have
00:32:30.23 languages arrested, both of them, in this case Chinese and English.
00:32:35.22 This is the age at which the patient acquired these languages,
00:32:38.20 and some of these patients can have sites with different languages,
00:32:42.24 or in this case, both sites arrested both languages.
00:32:48.15 So, the variability is enormous.
00:32:50.05 This is why, many times, you can't just do the patient sleeping.
00:32:55.07 You have to see. You can actually see the resection cavity right here.
00:32:58.17 Look how close we are to the areas of the speech. Just millimeters away.
00:33:04.02 This is a picture from the operating room,
00:33:06.08 and we have achieved a gross total resection of this tumor.
00:33:10.22 And this is the paper that we published a number of years ago,
00:33:13.08 and this is the overall results. As I was training, we were able to
00:33:17.02 do some number of patients that were bilingual,
00:33:20.23 in which we found several areas. As you can see,
00:33:23.11 Chinese and English, English and Spanish,
00:33:25.29 Punjabi and English, Turkish and English,
00:33:28.15 as well as Spanish and English.
00:33:31.06 So, there's an incredible amount of variability,
00:33:33.01 and this is why, if the tumor is here, or the tumor is here
00:33:36.16 in this vicinity, I would recommend that a patient most likely have
00:33:41.15 an awake craniotomy. This is a reconstruction of an MRI from the operating room.
00:33:46.17 What about the treatment?
00:33:47.22 Well, it turns out... This is a paper from Roger Stupp,
00:33:50.23 New England Journal of Medicine. I alluded to it in my prior talk.
00:33:53.28 "Radiotherapy plus Concomitant use of Temozolomide for Glioblastoma multiforme."
00:34:01.25 That means at the same time.
00:34:03.14 Most patients have it for 6 weeks. They have the chemotherapy every day,
00:34:07.13 they have the radiation therapy 5 days a week.
00:34:08.27 We start 2-4 weeks after surgery.
00:34:11.11 And they get radiation plus temozolomide at the same time.
00:34:15.14 Temozolomide is an oral medication.
00:34:18.07 And you can actually see, if we do that with a good, gross total resection of the tumor,
00:34:23.05 these patients tend to do much better than if we do radiation therapy alone.
00:34:28.08 This is an FDA - this is a government approved treatment for these cancers.
00:34:33.23 What about the summary of current treatments for malignant gliomas?
00:34:37.13 Well, if they're new, as you can see in this column, the type of tumor.
00:34:41.28 You can see in this column is the therapy.
00:34:44.09 If you have a glioblastoma multiforme,
00:34:47.11 which is a Grade IV -- this is the malignant cancer,
00:34:50.09 we have maximal surgical resection, plus radiation therapy,
00:34:54.10 plus concomitant and adjuvant temozolomide or the wafer, the so-called Gliadel...
00:35:01.24 and I'll show you a picture of this right now.
00:35:04.06 If it's an anaplastic astrocytoma, we also like to achieve a maximal surgical resection
00:35:09.24 with options after surgery of standard treatment or radiation
00:35:15.13 plus adjuvant use or temozolomide or temozolomide alone.
00:35:20.11 These are slightly different protocols.
00:35:22.24 What about an anaplastic oligodendroglioma, astrocytoma (Grade III)?
00:35:27.11 Well, you can actually see, maximal surgical resection,
00:35:30.00 with the options after surgery of radiotherapy alone,
00:35:35.00 temozolomide, PCV with or without radiation therapy.
00:35:39.18 What about recurring tumors?
00:35:41.29 These tumors are actually more complex in some cases,
00:35:45.18 but also some of these treatments do exist for them,
00:35:48.14 like reoperation of selected patients, and I'll show you an image
00:35:51.17 that the reoperation is very, very important for these patients.
00:35:56.11 At Johns Hopkins, we did a study a few years ago,
00:35:59.11 and we looked at radiation therapy with no Gliadel,
00:36:02.23 radiation therapy with Gliadel, or radiation therapy with temozolomide,
00:36:07.04 and a selected group of patients, we have used a combination of
00:36:11.03 surgery, with good resection as you can see right here,
00:36:14.20 with the intraoperative use of these little wafers that were invented
00:36:19.03 by one of my colleagues by the name of Henry Brem
00:36:22.13 that are called Gliadel. We put them in right at the time of the surgery,
00:36:26.19 so the patient is already getting chemotherapy
00:36:28.15 for the treatment. And then, we give them an oral medication
00:36:32.20 which, here, is the temozolomide.
00:36:34.22 And, in addition to that, the patients are also getting radiation,
00:36:39.04 and it seems that if we use a combination of good surgery,
00:36:41.20 followed by Gliadel and temozolomide and radiation,
00:36:46.01 these patients can survive up to 20 months.
00:36:50.02 And, as far as we know, in our experience, the number of complications
00:36:54.07 is very, very minimal on these patients.
00:36:57.28 I'll tell you something, and I'm going to wrap up in the next few minutes
00:37:02.21 with the actual cellular origin of these differentiated glial or stem cell progenitors.
00:37:08.01 There's been a fair amount of work in trying to understand how these tumors
00:37:13.23 begin and how they continue.
00:37:16.14 Well, this is the pathway from a low-grade oligodendroglioma
00:37:21.08 going all the way to an anaplastic oligodendroglioma,
00:37:25.25 in which, the median survival is 3-5 years.
00:37:28.23 If it's a low-grade oligodendroglioma,
00:37:33.10 the median survival is 5-10 years.
00:37:36.20 But these tumors can actually progress from a low-grade to a high-grade.
00:37:42.16 They're all in the spectrum of cancer. If you remember,
00:37:45.17 we mentioned that earlier. So, sometimes you can see a fair number of mutations
00:37:50.14 The one that I call to your attention is p53,
00:37:54.13 and as you can imagine, VEGF -- Vascular Endothelial Growth Factor overexpression.
00:38:01.23 A lot of these tumors have the marker for Olig2
00:38:05.27 expression, which is thought to be the cell of origin or one of the cells of origin
00:38:12.21 for the progression -- the origin and the progression of these tumors
00:38:16.20 from low-grade to high-grade. What about the next type of tumor?
00:38:20.04 The actual tumor that starts when the patient comes in to the clinic
00:38:26.01 is already a primary glioblastoma.
00:38:28.20 The median survival for those patients, as you can see,
00:38:31.19 is 12-15 months.
00:38:33.24 This is a devestating disease.
00:38:35.16 Once again, the most devestating cancer affecting the most beautiful organ in the body.
00:38:40.23 One of the overexpressions is the Epidermal Growth Factor Receptor overexpression in
00:38:47.02 over 60% of these patients.
00:38:49.04 These patients are devastated.
00:38:51.00 A lot of these tumors, they present like this.
00:38:53.28 And the best way that I can tell you is that a lot of my patients tell me
00:38:57.00 that this tumor is like driving in the desert
00:39:00.23 with your air conditioner on, and suddenly you get hit from the side
00:39:05.02 and your whole life changes all of a sudden
00:39:07.12 because of the diagnosis of one of these devestating tumors.
00:39:11.00 But some patients can start with a low-grade astrocytoma,
00:39:15.09 in which the median survival is 5-10 years.
00:39:17.23 It's in the spectrum of cancer.
00:39:19.00 And then, they can move on, if they recur,
00:39:21.28 to an anaplastic astrocytoma,
00:39:24.12 and then, potentially to a secondary glioblastoma,
00:39:28.14 which at that point, the median survival is much less.
00:39:32.13 So, that means that they can start with a low-grade tumor
00:39:34.20 and move all the way up to a high-grade tumor.
00:39:38.27 As you can see, the median survival varies, depending on where they start.
00:39:43.08 And the higher the grade, the less chance they have of surviving
00:39:48.23 for many years the disease.
00:39:50.23 Our work at Johns Hopkins and in San Francisco, where I trained,
00:39:55.07 has to deal with whether or not there is an origin
00:39:59.16 for these tumors and whether or not they are linked to parts of the ventricle.
00:40:03.09 Whether or not there's a cell of origin.
00:40:05.29 In 2004, we published this paper. If you want to hear more about it,
00:40:09.14 please tune in to my next segment of this series of talks.
00:40:13.10 We believe that potentially there's a series of cells that may be normal
00:40:19.19 neural stem cells that can potentially give rise to these malignant tumors.
00:40:25.20 That is still a working hypothesis.
00:40:28.26 What we do know, and this is based around the same time in 2004...
00:40:32.21 Our colleagues from Italy and our colleagues from Canada
00:40:36.10 published two different papers in two different journals
00:40:39.14 with similar results. That is, if they get tissue from the patient,
00:40:43.19 and they grow them as small spheres,
00:40:47.03 and they put them back on animals, those tumors look very much like
00:40:52.29 the tumor of the patient.
00:40:55.13 The same thing with our colleagues from Canada. They did something similar,
00:40:59.13 and what they found out is when they isolate using the marker CD133,
00:41:03.27 and they put these cells back in the mice,
00:41:07.09 they actually develop tumors that look like the parent tumor.
00:41:11.09 So, for the first time, alluding to the fact that there is potentially, within brain tumors,
00:41:17.12 a small population of so-called brain cancer stem cells --
00:41:22.04 brain tumor stem cells that can actually give rise to the tumor.
00:41:26.23 And those are the cells that no matter what we do,
00:41:29.21 through radiation and chemotherapy and whatever we throw at them,
00:41:32.22 they are probably surviving, and this is why these tumors are so devestating.
00:41:37.25 These are... This is a diagram based on a paper that I published a few years ago,
00:41:41.23 in which we looked at not only neural stem cells,
00:41:45.04 but also brain tumor stem cells and some of the similarities that they
00:41:48.21 share. And this is why we've been so interested in trying to understand
00:41:53.13 whether these neural stem cells can give rise to brain tumor stem cells.
00:41:57.27 They have incredible migratory capabilities.
00:42:01.11 They have regulation of pathways.
00:42:03.23 As you can see, brain tumor stem cells, they have the ability of long-term propagation
00:42:09.08 and dual phenotype labeling.
00:42:11.29 So, you have to be very, very careful in trying to understand this pathway
00:42:17.21 and trying to make sure that we make sure we understand the difference
00:42:21.12 between these two cell populations
00:42:22.22 because potentially we may be looking at a new way of treating brain cancer
00:42:28.07 in the future. So, let me tell you a few of the conclusions about
00:42:31.26 brain cancer. It's been just a little over 100 years since brain surgery
00:42:38.16 for any type of disease, but specifically for brain tumors, started.
00:42:42.04 We are at the embryonic stages, in my opinion,
00:42:45.18 of the development of new technology, new paradigms,
00:42:49.01 new ways of looking at brain cancer.
00:42:51.24 We have tumors that are considered to be non-cancerous
00:42:55.21 and tumors that are considered to be cancerous.
00:42:58.13 Within the cancerous family of tumors,
00:43:00.12 we have the low- versus the high-grade gliomas.
00:43:04.05 We have the primary versus the secondary tumors.
00:43:09.04 We have mutations that may potentially give rise to these tumors.
00:43:14.12 For us, surgery is the first and most important step
00:43:19.26 to control the disease in our patients.
00:43:23.19 It's not a cure.
00:43:24.13 The cure is only going to come from our future research.
00:43:28.20 But, within surgery, over the past 100 years,
00:43:31.21 we've been able to perfect techniques to map the brain,
00:43:35.05 techniques to be able to navigate the brain,
00:43:38.19 and most important, we've been able to do surgeries
00:43:43.25 on patients that are considered to be extremely technical in detail
00:43:49.26 and extremely challenging, such as awake craniotomies.
00:43:52.26 But this is not modern surgery.
00:43:54.26 If you look back at the picture that I showed you all the way back from Harvey Cushing,
00:43:58.16 we are standing on the shoulders of giants.
00:44:01.27 Brain tumor dispersal, which is the main challenge that we face,
00:44:05.23 appears to be, and appears to have, a population of cancer stem cells
00:44:11.08 that gives rise to these malignant brain tumors.
00:44:14.05 And they share common characteristics.
00:44:16.27 So, our future challenge is going to be to understand
00:44:20.12 this disease and the implications and hopefully develop new techniques.
00:44:25.23 I thank you very much for your attention.
00:44:27.25 If you want to learn more about brain tumor stem cells,
00:44:30.17 that will be our next segment. Thank you.
00:44:33.06

Part 2: Stem Cells and Brain Tumors

00:00:01.21 Hello. My name is Alfredo Quinones-Hinojosa. I'm an associate professor
00:00:05.21 of Neurosurgery, Oncology, Cellular and Molecular Medicine, and Neuroscience
00:00:10.07 at Johns Hopkins University.
00:00:12.11 Today, I have the pleasure of speaking to you about the issue of stem cells and brain tumors.
00:00:18.11 The question is whether or not there is a cell
00:00:24.20 that has given rise to a brain cancer,
00:00:29.11 and whether or not that cell was a normal neural stem cell
00:00:33.10 that has given rise to a brain tumor,
00:00:36.10 or whether or not there was a brain tumor stem cell
00:00:40.13 population within brain cancer.
00:00:42.21 And we're going to go ahead and explore this.
00:00:45.02 I'll tell you a little bit about history.
00:00:47.08 In my opinion, the most beautiful organ in the body is the brain,
00:00:50.15 and this is a 3-dimensional reconstruction of an MRI.
00:00:53.05 And what you do not see right here
00:00:56.28 is that, in the left side of the brain, which is this area right here --
00:01:01.01 remember the image is flipped.
00:01:03.20 We have done this, right here, you know, in this case label L for left
00:01:08.29 and you're looking, yourself, at this brain, face-to-face,
00:01:12.00 like this. This is the left side. Underlying this,
00:01:15.08 is a very dangerous brain tumor,
00:01:18.12 also known as a glioblastoma multiforme.
00:01:21.12 Over 100 years ago, Santiago Ramon y Cajal won the Nobel Prize in Physiology and Medicine
00:01:27.07 because he was able to contribute greatly to the field of neuroscience
00:01:31.27 by looking at the different types of cells that make the brain.
00:01:37.00 He said that we had a harsh decree
00:01:40.27 that everything may die, and nothing may be regenerated in the adult central nervous system.
00:01:47.08 He left the possibility open for pathological diseases.
00:01:52.03 He was a pathologist by training and became one of the great neuroscientists in the world.
00:01:58.20 Over the next 30-40 minutes, I will take you over some of the history
00:02:04.11 of the controversy over the adult neurogenesis,
00:02:06.19 the difference between the human vs. the rodent stem cell niche --
00:02:13.00 more specifically, the sub-ventricular zone.
00:02:16.09 I will take you over whether or not there are stem cells that are found
00:02:21.20 in the human brain, and whether or not
00:02:24.08 there are stem cells found in human cancer.
00:02:29.03 The question that still remains is whether or not a neural stem cell or a stem cell
00:02:34.18 may give rise to a brain tumor stem cell, and that is work in progress,
00:02:40.01 and I will elaborate on a little bit of that.
00:02:43.11 What about this issue of the controversy of adult neurogenesis?
00:02:46.20 Well, it turns out that dating back to the early 1900s,
00:02:51.15 Santiago Ramon y Cajal knew that we had limitations in technology.
00:02:56.07 He said once that none of the methods used by these investigators
00:02:59.22 are capable of distinguishing absolutely a multiplying neuroglia cell
00:03:07.06 from a small mitotic neuron.
00:03:10.03 So, the question is whether or not there were new neurons
00:03:13.01 being formed int he adult mammalian brain.
00:03:16.27 By the 1960s, Joseph Altman, by doing a study with thymidine autoradiographic evidence,
00:03:26.26 he was able to find new neurons in the adult rat and cat.
00:03:33.25 But, it would take a few years later, by the 1970s,
00:03:37.12 when Michael Kaplan, he combined thymidine labeling
00:03:41.18 and electron microscopy. This is the early research and the early utilization
00:03:48.02 of electron microscopy that confirmed Altman's claims
00:03:53.16 by showing mitotic neuronal precursors lining the lateral ventricle.
00:03:59.05 But, people still were very skeptical.
00:04:02.11 It was kind of hard to understand and to believe
00:04:05.26 that indeed, new neurons are being produced in the lateral ventricle of the mammalian brain.
00:04:11.29 By the 1980s, Nottebohm and colleagues, out of New York,
00:04:16.23 were, by doing some really eloquent studies
00:04:20.17 in the avian brain, they were able, through a series of experiments, to show several things.
00:04:27.15 The production of new cells with thymidine labeling.
00:04:31.28 They were able to show that these new cells were not only neurons,
00:04:36.05 but they were also receiving synapses.
00:04:38.22 And most importantly, these neurons that were receiving synapses
00:04:42.23 responded to sound with action potential.
00:04:46.24 Yet, people were very skeptical about the issue
00:04:52.07 of neurogenesis in the avian brain
00:04:55.14 because they said that it was not the mammalian brain.
00:04:58.10 So, by the 1990s, work in the rodent,
00:05:01.21 out of several laboratories around the world, they began to unravel
00:05:06.16 and teach us more about this issue about the controversy of neurogenesis.
00:05:11.08 By 1997, a group of investigators led by Dr. Arturo Alvarez-Buylla,
00:05:17.14 also out of New York and subsequently out of California,
00:05:21.11 was able to elucidate the organization and cytoarchitecture
00:05:26.18 of the rodent sub-ventricular zone.
00:05:29.14 But 1999, a very important discovery that was also controversial --
00:05:34.23 several groups believing there were probably ependymal cells
00:05:37.28 that were responsible for neurons. And Arturo and his group,
00:05:42.11 believing that it was actually astrocytes, were able to show
00:05:46.00 that adult neural stem cells come actually from astrocytes in the rodent brain.
00:05:52.12 What was not known at this point
00:05:55.29 was whether or not this was also true for the human brain.
00:06:00.03 It was even less known the difference in this stem cell niche --
00:06:04.29 the sub-ventricular zone -- between the human and the rodent.
00:06:09.22 And that's the next portion of this discussion.
00:06:12.12 Several years later, by the year 2003-2004,
00:06:19.04 as Arturo and his group, and myself involved in some of these studies,
00:06:23.15 we began to unravel some of the mysteries of the organization
00:06:28.28 of the human sub-ventricular zone.
00:06:31.20 We began to look at markers of migration, in this case,
00:06:35.20 PSANCAM and markers of proliferation, KI67,
00:06:40.15 and markers of neuronal precursors, TuJ1.
00:06:44.14 And we looked at several parts of the brain.
00:06:47.07 This is anterior horn, the body of the ventricle,
00:06:49.19 the other parts of the ventricle, as you can see,
00:06:53.01 all the way to the temporal horn, right here on the bottom.
00:06:56.07 And what you can see, actually, not only the organization
00:07:00.09 was different -- there was evidence of proliferation, migration,
00:07:03.20 but also we found evidence of some neurons struggling
00:07:07.18 into this area of the sub-ventricular zone,
00:07:10.21 going up and down.
00:07:12.18 So, after many years of looking at the organization
00:07:15.12 of the rodent sub-ventricular zone, done by many groups around the United States
00:07:19.22 and the world,
00:07:20.10 we began to look at the organization of the human sub-ventricular zone.
00:07:25.05 And you can actually see here... in red
00:07:27.18 is GFAP, and in blue is DAPI.
00:07:30.11 For the rodent sub-ventricular zone, you can actually see
00:07:33.22 GFAP in green, double cortin in red, and DAPI in blue.
00:07:38.10 And then there's a cartoon illustration between the human sub-ventricular zone
00:07:43.06 and the rodent sub-ventricular zone.
00:07:45.17 In the rodent sub-ventricular zone, not only is the brain a little bit more
00:07:49.16 lissencephalic in sculpture. That means that it has less grooves
00:07:53.18 as compared to the human brain. But, in the area of the sub-ventricular zone --
00:07:57.20 that is the lateral wall of the ventricle right here.
00:07:59.15 This is an amplification. You can actually see a group of cells
00:08:03.12 just coming out. Also known as a rostral migratory stream.
00:08:07.11 And these astrocytes are completely welded against the epyndemal zone.
00:08:12.16 Yet, in the human brain, there is the epyndemal zone right here,
00:08:16.12 which is called layer 1. Then layer 2 is a hypocellular gap.
00:08:20.03 Then layer 3 is a ribbon of astrocytes.
00:08:23.08 And then there is a transition to the parenchyma.
00:08:26.15 Striking differences between the organization of the human sub-ventricular zone
00:08:31.04 and the rodent sub-ventricular zone.
00:08:34.06 So, we got interested in our laboratory to further elucidate
00:08:37.28 the organization of the human sub-ventricular zone.
00:08:40.20 We went on to do these very similar studies in the fetal human brain.
00:08:46.17 And indeed, it appears to be that the lateral ventricle may be connected also
00:08:52.00 to the rostral migratory stream, all the way down
00:08:55.18 against the olfactory bulb. This is a so-called
00:08:57.17 sagittal section along this region that is slightly oblique right here
00:09:02.23 and a little bit inclined, as you can see
00:09:04.04 right here, and we were able to study different regions of this part of the brain,
00:09:09.18 trying to understand how is the fetal brain and the human brain organized
00:09:15.16 as compared to the rodent brain.
00:09:18.28 Is there a population of cells that are migrating?
00:09:22.09 It turns out that we found some evidence that indeed
00:09:26.18 there are some cells that appear to be migrating outside of this region.
00:09:31.03 Not necessarily the same way that they appear to be migrating in the rodent brain,
00:09:36.07 from the ventricle down to the olfactory bulb,
00:09:39.00 but indeed some of these cells appear to be migrating in groups,
00:09:43.06 and they're surrounded by these glial cells. This is a confocal microscopy
00:09:47.23 of such a region in the human fetal brain,
00:09:51.02 and unfortunately, our group, has not been able to find evidence
00:09:55.19 of a similar type of migration in the human brain
00:09:58.27 per se, in the human adult brain,
00:10:02.09 but other groups around the world have claimed that this does indeed exist.
00:10:06.14 So the question is, if migration exists in the human brain,
00:10:10.05 could we learn something about that migration
00:10:13.27 that will help us understand why brain tumors are so migratory?
00:10:18.02 This is an image that I will show you of a small piece of human fetal brain
00:10:23.03 that is put on Matrigel, in which you're going to see evidence of migrating cells
00:10:27.23 surrounded by glial sheets.
00:10:30.07 And this is the picture, right here. This is the movie.
00:10:32.21 You can actually see -- this is from own our laboratory -- cells migrating,
00:10:36.21 and this is human fetal brain.
00:10:38.07 They're migrating out, and they are surrounded.
00:10:42.05 And we've done all these immunostainings to be able to see that, indeed,
00:10:45.26 the human fetal brain may have some similarities in regard to migration
00:10:51.13 as compared to the rodent brain.
00:10:55.05 We have done similar studies, as you can imagine, with human brain tumors
00:10:59.15 and we are in the process of trying to unravel some of the mysteries
00:11:03.16 that human brain tumors use for migration.
00:11:07.04 I'll take you. So, we have gone over the controversy of adult neurogenesis
00:11:11.26 and I think it's clear that the mammalian brain does have the ability
00:11:16.00 to generate some neurons, at least in the rodent brain.
00:11:18.29 And similar evidence may actually be becoming more clear
00:11:23.25 in the adult human brain.
00:11:26.00 We know that the stem cell niche -- in this case the sub-ventricular zone --
00:11:30.09 is different between the human and the rodent.
00:11:33.04 The question is whether or not there are stem cells
00:11:36.09 in the human brain, and whether or not there are stem cells in human cancer.
00:11:40.03 So, could it be that there are human adult neural stem cells?
00:11:45.02 By the 1990s, Steve Goldman and his colleagues, they did several studies
00:11:49.11 and published a paper about finding adult neurogenesis
00:11:53.24 from the temporal horn sub-ventricular zone in vitro.
00:11:57.11 This was from temporal horn surgeries, in which they did temporal lobe resections
00:12:04.12 and were able to culture this tissue and create neurons
00:12:07.10 for the first time, showing that indeed, at least in the petri dish,
00:12:11.06 it's possible.
00:12:12.12 By the 1990s, Gage and his colleagues, showed a study
00:12:16.08 by looking at brains post-mortem -- they call it in vivo, but post-mortem --
00:12:22.08 in which they showed neurogenesis in the adult human hippocampus.
00:12:27.11 And I am in the right side of the hippocampus right now
00:12:29.28 I'm showing one specific picture, and what you can actually see
00:12:33.06 right here, in this particular cell right here that is marked
00:12:37.02 with two markers -- red is NeuN as you can see right here
00:12:41.13 and green is BrdU, so this appears to be the formation of a neuron.
00:12:46.19 These patients had actually received BrdU for the treatment of other diseases.
00:12:51.29 They passed away, and this group was able to obtain their brains
00:12:56.09 and do these studies. For the first time,
00:12:59.01 freezing these tissues in time, they were able to find evidence of new neurons
00:13:04.14 being formed in the adult human hippocampus.
00:13:09.14 So, we ask ourselves the same questions.
00:13:13.14 By 2004, we asked -- we published a paper in which we asked ourselves the questions:
00:13:18.09 The adult human sub-ventricular zone could potentially have neural stem cells?
00:13:24.07 We actually obtained the specimens from the operating room.
00:13:27.22 We looked at specifically specimens from the sub-ventricular zone,
00:13:31.08 and we were able to form these beautiful, small spheres.
00:13:35.11 We called them neurospheres.
00:13:37.05 We purified these sub-ventricular zone astrocytes.
00:13:41.09 That means, through a procedure, we shake the cells,
00:13:44.07 and at the end, in the petri dish,
00:13:46.07 we only leave astrocytes. And we were able to create even more
00:13:50.25 neurospheres as compared to those episodes in which we did not purify the astrocytes.
00:13:56.23 And we obtained astrocytes from the cortex and the striatum.
00:14:01.05 We had absolutely no evidence of sphere formation,
00:14:04.14 telling us for the first time that indeed there's got to be something peculiar
00:14:08.12 in the astrocytes that are found in the sub-ventricular zone,
00:14:12.15 because not only when we purify them
00:14:15.01 we find more neurospheres, but
00:14:19.02 also when we have the same astrocytes or similar astrocytes from the cortex and striatum,
00:14:24.10 we found no evidence of neurospheres.
00:14:26.17 This is the picture of one of such neurosphere.
00:14:29.26 And not only that, when we put them in a special media, we were able to form
00:14:35.07 the 3 lineages: in this case, neurons,
00:14:37.20 in this case oligodendrocytes, as you can see right here,
00:14:41.24 and astrocytes. So, from one of these spheres,
00:14:45.06 from the sub-ventricular zone,
00:14:47.05 we found the capability of these cells --
00:14:50.24 this is a sphere that came from a single cell that was an astrocyte.
00:14:55.08 It was a GFAP-positive cell,
00:14:57.25 and we differentiated the cells, we were able to produce 3 lineages. Once again,
00:15:03.09 astrocytes, neurons, and oligodendrocytes.
00:15:07.11 But that wasn't enough. The question was can
00:15:10.25 human sub-ventricular zone astrocytes
00:15:14.10 produce neurons without the effect of growth factors?
00:15:19.06 So, what we did right here, is we provide an environment
00:15:22.19 in which we use astrocytes from the human brain,
00:15:25.24 and then we got one astrocyte from the sub-ventricular zone,
00:15:30.23 and we dropped it in here
00:15:32.14 to see whether or not, without putting exogenous growth factors,
00:15:37.06 we could actually produce a neuron.
00:15:40.00 And I'm inside of one of these experiments, and you can actually see
00:15:42.24 in red, a beautiful neuron that has been formed from an astrocyte
00:15:48.03 that was derived from the sub-ventricular zone
00:15:50.15 without the use of growth factors.
00:15:52.25 We tried to do the same from cortical and striatal astrocytes,
00:15:57.27 and we were unable to produce a neuron.
00:16:00.25 Once again, telling us that there is something about the sub-ventricular astrocytes
00:16:05.25 that makes those cells peculiar and able
00:16:09.25 to produce neurons in the actual human brain.
00:16:13.14 Now, all of this was done in the petri dish,
00:16:17.18 and yet we were able to find, for the first time,
00:16:21.19 that in the region of the lateral ventricle,
00:16:24.06 as you can actually see right here, there are
00:16:26.04 several regions -- this was actually after studying a lot of specimens,
00:16:30.29 not only from the operating room, but also from post-mortem tissue,
00:16:36.03 we were able to find that in the lateral ventricle
00:16:38.25 of the human brain, there is a specific population of astrocytes
00:16:43.23 that can give rise, not only to those beautiful spheres,
00:16:47.16 but also to neurons, oligodendrocytes, and astrocytes,
00:16:51.17 and most importantly, even without growth factors, we can actually
00:16:56.06 produce a single neuron.
00:16:58.12 So, indeed, there is a possibility, up until the present,
00:17:02.19 what we didn't know before, that the human brain
00:17:05.16 in the petri dish, has the ability to produce neurons.
00:17:10.03 So, there's probably a cell population that we call stem cells
00:17:15.19 within this area of the sub-ventricular zone.
00:17:18.01 Other groups have continued to look at this cell population within the hippocampus,
00:17:25.01 and they're continuing to move this field forward.
00:17:28.11 What about the issue of stem cells in human cancer?
00:17:31.22 That is something that has been obviously one of the greatest challenges
00:17:36.17 that we have had, because cancer is still the most devestating disease
00:17:40.29 known to humans. In my opinion, the most beautiful organ
00:17:45.22 affected by the most devestating cancer.
00:17:50.04 One of the problems that we have, first of all,
00:17:52.24 is that we are dealing with tumors that come from the brain,
00:17:56.13 the so-called intraaxial tumors.
00:17:58.12 We can have all the way from low-grade gliomas (LGGs)
00:18:02.03 to high-grade gliomas (HGGs).
00:18:05.10 Low-grades to high-grades. They're all in the same family of cancers.
00:18:09.05 All the way from the low-grade to the high-grade.
00:18:11.07 I believe the lower the grade, the longer the survival of the patient.
00:18:15.11 The higher the grade, the more devestating it is for the patient.
00:18:20.07 The limitations are that we can potentially in surgery be able to resect
00:18:26.19 this mass that we can see in the operating room.
00:18:30.27 The problem is that by the time these patients get the diagnosis of brain cancer,
00:18:35.00 specifically if it is a high-grade glioma,
00:18:37.23 many cells have actually migrated all the way to the contralateral part of the brain.
00:18:44.19 And I tell you this is how devestating -- this is a mass murder.
00:18:48.29 Approximately 20,000 people in the United States are newly diagnosed
00:18:54.02 with the primary brain cancer.
00:18:57.20 That is the cancer that I just showed you.
00:18:59.13 That is a cancer that comes specifically from the brain.
00:19:02.28 And about half of those patients die every year
00:19:07.08 as a result of these malignant tumors.
00:19:10.06 That is specifically the gliomas -- that's the kind of tumor that we're discussing.
00:19:15.22 We have looked at this issue in our laboratory.
00:19:18.13 You know, I was interested to try to understand whether or not there was a relationship
00:19:22.18 between glioblastoma multiforme and the lateral ventricle.
00:19:26.24 So, remember, we study the lateral ventricles in the normal human brain,
00:19:30.04 and we know that there is a potential population of
00:19:32.19 cells that we call the stem cells.
00:19:34.16 So, can these potential stem cells give rise to these tumors?
00:19:38.13 Well, we've got to take one step at a time.
00:19:40.26 So, what we did, is we went back to our database at Johns Hopkins,
00:19:45.05 and we looked at the percent survival
00:19:48.28 and the months, right here, and we looked at two types of patients:
00:19:53.18 those that involved the sub-ventricular zone,
00:19:55.27 which is the dark line right here,
00:20:00.29 as you can actually see.
00:20:02.03 And then we looked at those patients that had no involvement of the sub-ventricular zone.
00:20:06.24 And this is this dotted line right here.
00:20:09.28 And we looked at the survival. What we noticed is those patients
00:20:13.13 that have tumors that is involved in the sub-ventricular zone,
00:20:16.21 which is this right here, which is this type of tumor right here,
00:20:20.03 survived only 8 months.
00:20:23.17 Versus those patients that had no involvement of the sub-ventricular zone,
00:20:28.10 which is this type of tumor, right here, not near the ventricle right here.
00:20:32.23 Those patients tend to survive 11 months. And this is the Kaplan-Meier curve.
00:20:38.01 So, for the first time, giving us an idea that potentially within this area,
00:20:43.18 there may be a population that is either contributing
00:20:47.08 or potentially originating some of these tumors.
00:20:50.16 That is still a working hypothesis.
00:20:52.18 The working hypothesis is straight forward.
00:20:56.00 How do tumors get formed?
00:20:57.14 Do tumors come in from the transformation of a neural stem cell
00:21:02.00 or a neural progenitor cell that is then transformed
00:21:05.14 into a brain tumor stem cell and then gives rise to these devestating tumors?
00:21:10.17 Are there epigenetic and genetic alterations that give rise to this transformation?
00:21:16.24 Is there a potential de-differentiation
00:21:20.06 between a neuron, an astrocyte, or an oligodendrocyte giving rise
00:21:25.04 to these neural progenitor cells, which in turn gives rise
00:21:29.14 to a brain tumor stem cell?
00:21:31.21 That is all work in progress.
00:21:34.13 The bottom line is that these tumors right here
00:21:37.10 are devestating, and the way that we're looking now at the potential
00:21:41.10 etiology by transformation of either neural stem cells or progenitor cells
00:21:45.27 giving rise to these brain tumor stem cells is absolutely
00:21:50.12 giving us the hope that we need that potentially one day
00:21:55.02 we'll be able to manipulate the system and be able to have a positive effect on our patients.
00:22:00.22 I show you, what around 2004, when we published our paper
00:22:04.20 in Nature,also showing that humans do have in the lateral ventricle
00:22:08.25 these neural stem cells that give rise to neurons
00:22:12.06 contributing to our understanding of the human sub-ventricular zone.
00:22:16.01 Around the same time, a group from Italy, and a group from Canada,
00:22:21.16 they showed that, indeed, when we obtain tissue from
00:22:24.27 the operating room, and we obtain the tumors, and then we grow them.
00:22:28.23 Tumors, either as little spheres, the so-called neurospheres,
00:22:33.23 they look exactly like the neurospheres, but they're called tumorspheres.
00:22:37.14 Or we isolate these cells based on CD133.
00:22:42.24 And we go ahead and put either the spheres or the cells back
00:22:47.06 in the rodent brain, these rodent brains produce tumors
00:22:52.13 that look exactly like the tumor of the patient.
00:22:56.03 And since then, other groups (ourselves included)
00:22:59.02 have actually duplicated some of those studies.
00:23:01.27 So, for the first time, giving us the hope that indeed
00:23:06.11 in the end, potentially these tumors are actually being able to be studied
00:23:13.05 when we obtain the tissue from the patient and bring it into the laboratory.
00:23:17.22 So, for the first time, beginning to make our patients part of not only the diagnosis,
00:23:22.07 but also the potential treatment
00:23:24.08 and making them part of history.
00:23:26.07 These tumors look much better, and they resemble much better
00:23:30.24 the parent tumor than some of the cell lines that we have used
00:23:33.26 for several decades now.
00:23:35.16 Now, there are similarities between the neural stem cells
00:23:39.24 and the brain tumor stem cells,
00:23:41.16 all the way from the migratory capabilities to the signaling.
00:23:45.12 And you can actually see some of these similarities right here.
00:23:48.22 What makes the brain tumor stem cells peculiar
00:23:52.23 is the fact that they seem to have a much more long-term propagation as well as
00:23:57.16 dual phenotypic labeling. That means that
00:23:59.10 they can actually mark with several markers.
00:24:02.17 Now, this is potentially what is making us think that
00:24:08.08 maybe neural stem cells, they do have to do something with brain tumor stem cells.
00:24:12.15 Once again, this is a working hypothesis that I think that potentially in the future,
00:24:17.11 we will be able to systematically begin to understand a little bit more.
00:24:23.00 What we do know today is that from the sub-ventricular zone,
00:24:26.27 from these astrocytes, we can form these spheres, and these spheres can in turn
00:24:32.10 give rise to the three lineages: neurons, oligodendrocytes, and astrocytes,
00:24:36.13 that you can actually see right here.
00:24:38.00 What we do know today is that if we obtain tissue from the operating room
00:24:43.01 from our patients, as we can grow one single cell
00:24:46.15 into a sphere, and that sphere can ultimately go back into the animal,
00:24:51.03 those tumors resemble the tumor that the patient originally had.
00:24:56.10 So, potentially giving us an opportunity to have a much better
00:25:00.21 model to study brain cancer, and that's exactly what we have done
00:25:05.14 in our collaborations, some of our work.
00:25:07.13 And I'll go over a couple of these studies.
00:25:09.09 For instance, this is a paper that we just published not too long ago,
00:25:13.21 actually in 2009, where we looked at the Delta/Notch-like
00:25:19.09 epidermal growth factor-related receptor.
00:25:21.26 These are tumors that were derived from glioblastoma multiforme neurospheres.
00:25:27.05 And, as you can see right here, this is the tumor
00:25:30.09 with no treatment. This is the tumor with treatment.
00:25:34.28 In this case, right here, this is the tumor value, which you can actually see right here.
00:25:39.29 These are the two different groups, and you can actually
00:25:42.09 see significant differences.
00:25:44.10 Once again, illustrating the principle that we can dream of manipulating the system.
00:25:52.23 and very systematically begin to understand what are the growth factors, receptors,
00:25:59.06 that have an influence on this tumor formation.
00:26:02.15 I'll take you through another study that we have done
00:26:05.10 that is the Kruppel-like Family of Transcription Factor 9,
00:26:10.21 a differentiation-associated transcription factor that
00:26:14.08 suppresses Notch I signaling and inhibits glioblastoma-initiating stem cells.
00:26:20.16 This is the actual image right here. This is the control.
00:26:23.29 You can see the massive tumor, similar to the tumor of the patient,
00:26:28.14 and when we treat these tumors,
00:26:30.18 for this factor specifically, you can see much less tumor formation
00:26:38.16 in the animal, in the rodent model.
00:26:41.10 And you can actually see right here, in this axis
00:26:45.25 is nothing else, but the actual significant difference between the control
00:26:50.27 and those treated in regards to the tumor size right here.
00:26:54.23 And right here is the Kaplan-Meier for the survival of these two groups.
00:26:59.17 That is the control and the animals that are treated.
00:27:02.26 And it's a significant difference, once again giving us
00:27:05.24 the hope that we can learn from this disease, that we can learn from
00:27:10.13 these cells, that what we learn from these cells or from these deceased
00:27:14.29 can potentially one day be applied to our patients,
00:27:19.06 giving us this view.
00:27:20.06 And I'll leave you with this last paper from PNAS
00:27:23.02 that we just published a few months ago, in which we look at
00:27:26.15 c-Met signaling inducing a reprogramming network
00:27:30.25 and supporting a glioblastoma stem-like phenotype.
00:27:32.16 And you can actually see the control -- very large tumor
00:27:36.04 and those treated right here, giving us the tumor area.
00:27:39.29 The difference between these two right here.
00:27:41.27 Once again, for the first time, giving us the ability to manipulate the system.
00:27:46.27 I think, now through the studies that not only our group, but other groups around the world
00:27:51.18 are doing on these spheres... on these tumor spheres,
00:27:55.20 that when they are put back into animals, those tumors look like the parent tumor,
00:27:59.14 we will be able to unravel the mysteries, the signaling,
00:28:05.05 the characteristics that these tumors have, and one day
00:28:07.19 we will be able to produce new therapeutics that will have an effect in our patients.
00:28:14.29 So, I conclude by telling you that there is
00:28:18.08 adult neurogenesis in the mammalian brain.
00:28:21.18 There is a stem cell niche, specifically the sub-ventricular zone,
00:28:26.01 which is different between the human and the rodent mammalian brain.
00:28:30.23 And that's actually a very important difference, because
00:28:33.16 throughout the years... throughout decades,
00:28:37.03 we have continued to study formation of tumors
00:28:39.24 in the rodent brain -- formation of rodent tumors in the rodent brain.
00:28:45.05 And I think that it's still a necessity to do so
00:28:48.19 to continue to unravel some of the common mechanisms
00:28:51.01 that the rodent brain may have with the human brain.
00:28:53.25 But I do also think that it is very, very important
00:28:57.12 that we continue to do human tissue research,
00:29:02.20 and that is because there are striking differences between the human and the rodent,
00:29:08.13 and we have to try to understand from both simultaneously.
00:29:12.06 They do exist. Stem cells do exist
00:29:17.13 in the human brain. We know that. We have done that ourselves.
00:29:21.24 Other groups. They exist in the sub-ventricular zone, at least in the petri dish.
00:29:26.03 They exist in the hippocampus, and that is something very, very important to consider
00:29:31.04 for us to understand and to use this capability
00:29:34.09 for future regenerative medicine.
00:29:36.21 Stem cells also do exist in human cancer,
00:29:40.26 and we are beginning to unravel the mysteries
00:29:43.12 and the ways to manipulate this system presently.
00:29:47.23 Whether neural stem cells give rise to tumors is still not known.
00:29:52.21 I think this is a working hypothesis.
00:29:55.28 What is known is of a population of cells within tumors
00:29:59.18 that behave like stem cells.
00:30:02.02 And this is actually very, very important for us to be able to understand
00:30:06.00 not only the etiology, but the potential progression of brain cancer.
00:30:11.00 I think that the future is bright,
00:30:14.08 and we will continue with the quest to find the etiology
00:30:19.07 of brain tumors, so potentially one day,
00:30:22.20 we will be able to find better ways to treat our patients.
00:30:28.00 I thank you very much. I thank all the people that have supported our work
00:30:32.02 throughout the years, including the NIH, Howard Hughes,
00:30:35.06 the Maryland State Stem Cell Research Fund.
00:30:39.20 And most importantly, I thank my group.
00:30:43.14 This is a group of young scientists that have allowed
00:30:45.13 me to learn from them and allowed me to teach them a little bit of what I know,
00:30:50.03 and together, we're trying to find hope for our patients.
00:30:54.01 I have the most beautiful job in the world.
00:30:55.17 Every day I work not only as a brain surgeon,
00:30:58.02 giving my patients hope in the operating room,
00:31:00.25 but hopefully giving them hope also outside of the operating room.
00:31:04.21 Thank you very much.

Videos in this Talk

Part 1: Brain Tumors
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad
Part 2: Stem Cells and Brain Tumors
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad

Speaker: Alfredo Quiñones-Hinojosa

Total Duration: 1:16:03

Recorded: July 2011

All Talks in Neuroscience

Talk Overview

In part 1, Quiñones-Hinojosa discusses the history of brain tumors, different types of tumors (non-cancerous vs cancerous) and what this means for treatment and prognosis. He then focuses on a specific type of tumor, glioblastoma multiforme, and outlines what oncologists and surgeons have learned about this cancer over the past 30 years and how this information has influenced treatment. He closes with a brief overview of what is known about brain tumor stem cells.

In the second part of his talk, Dr. Q presents results from his lab and others that are beginning to provide insight into understanding brain tumor stem cells and the key role they play in both causing and possibly curing brain cancer.

Speaker Bio

Alfredo Quiñones-Hinojosa

Dr. Quiñones-Hinojosa, affectionately known as Dr. Q, is an Associate Professor of Neurosurgery and Oncology, Neuroscience and Cellular and Molecular Medicine at Johns Hopkins University School of Medicine. He is also director of the Brain Tumor Surgery Program and the Brain Tumor Stem Cell Laboratory where he investigates the role of brain stem cells in… Continue Reading

Comments

Brandon says

April 30, 2019 at 10:15 am

Im a student doing research on you Alfredo Quinones Hinojosa
My comment is what kind of research did you do for cell research.

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Part 1: Brain Tumors

Part 2: Stem Cells and Brain Tumors

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Alfredo Quiñones-Hinojosa

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Alfredo Quiñones-Hinojosa

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