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Melanie Cole (host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And joining me today is Dr. Elias Sayour. He's an Associate Professor of Neurosurgery and Pediatrics, the principal investigator of the RNA Engineering Laboratory at the Preston A. Wells Jr. Center for Brain Tumor Therapy and the Pediatric Cancer Immunotherapy Initiative at the University of Florida College of Medicine. He's here to highlight pediatric brain tumors.

Dr. Sayour, thank you so much for joining us today. I'd like you to start by telling us a little bit about the prevalence of pediatric brain tumors and how the treatments have evolved over the years. Tell us a little bit about what has been the thought previously and what are we looking at and doing now?

Dr. Elias Sayour Sayour: Well, thank you, Melanie, for having me. It's an honor and a privilege to be here and speaking to you all. So, pediatric brain tumors are really one of the most common cancers that children are diagnosed with. About 10,000 children in the United States under age 15 will be diagnosed with cancer in the United States. And in many ways, because we've gotten so good at curing other cancers, primarily leukemia, which is the most common childhood cancer, the brain tumors are now the number one cause of cancer death in children. And so, we have a bit of work to do to improve those outcomes.

And pediatric brain tumors really have been difficult to manage in large part because of the blood-brain barrier, which is difficult to get therapies past. And so, the mainstay of therapy has largely been surgery, radiation, which can be a challenge sometimes for children because of the developing brain. We tend not to want to radiate children who are less than three years of age. And so, chemotherapy has largely overtaken radiation as a primary way of managing a lot of these tumors, the malignant brain tumors that is, to help ameliorate some of the effects and buy time really for radiation and other therapies as they grow up.

Melanie Cole (host): Well, I'd like you to speak about how it presents clinically if pediatricians might be the first providers, if a child is having some of these signs and symptoms. I'd like you to speak about those. And then, you can get into classification, how it really is diagnosed.

Dr. Elias Sayour Sayour: So, signs and symptoms, children with a malignant brain tumor can present with different signs and symptoms. This really depends on where the tumor is. So if we could divide the brain into two portions, an upper portion and a lower portion. The upper portion of the brain, if there's a tumor there, a child could present with a seizure. The lower part of the brain, a child could present with the eyes could start to deviate perhaps to one side or another. For brain tumors in children, other signs could include imbalance. This can especially be true if there's a tumor in the lower part of the brain.

Other signs include nausea, vomiting, certainly morning nausea, any sort of imbalance, uncoordination. All of those things could be concerning. It's really the constellation of symptoms that a child could present with that would make one a little concerned about something like this. And that would warrant imaging.

I think some of the followup questions you asked were regarding classification, if I understood that correctly. In terms of classification, we used to refer to these as either benign or malignant. I don't like the term benign because benign, really, it has this connotation that it's not a big deal. And certainly, if you have a benign brain tumor in an area that cannot be removed surgically, that could be problematic. But in general, we have referred to these as benign or malignant.

And by benign, the most common ones tend to be what we call low-grade gliomas. The bulk of these are a disease called juvenile pilocytic astrocytoma. And those can be resected and it can be fully resected, a child can just be monitored to make sure it doesn't recur. But oftentimes, these low-grade gliomas, they arise in regions that you can't resect, especially if it's in the brainstem or the middle part of the brain, that could be very challenging. And so, they're very slow-growing and so often, we can treat them with chemotherapy to try to melt them away. Targeted therapies are becoming more and more common where we would find a target that's present on a patient's tumor and then go after it with a small molecule inhibitor that just specific to that patient's individual target. Sometimes that helps for these slow-growing tumors.

This is in contrast to what we refer to the malignant tumors. These tumors they're not slow-growing. They can be highly invasive. They can invade the architecture of the brain causing a lot of damage. And these tumors require a bit more aggressive management. These include diseases like medulloblastoma. Medulloblastoma is the most common malignant brain tumor in children. Other malignant brain tumors include rhabdoid tumor, neuroectodermal tumors, appendamomas, malignant gliomas, which includes the dreaded diffuse intrinsic pontine glioma, which is a very, very difficult tumor to manage.

And so without getting into each and every one of these, the management is largely surgical, if surgery is an option. Unfortunately, for the diffuse intrinsic pontine glioma, these are usually inoperable. The most you could do is biopsy because these tumors are located in the brainstem. And the brainstem, it controls breathing, so you can't do full resections when these are arising from within the brainstem. Other tumors such as medulloblastoma, rhabdoid tumor, primitive neuroectodermal tumors, those tend to be managed with chemotherapy, radiation as well. Again, we would try to defer radiation into children who are three years or older to prevent some of the deleterious effects on growing brains. But those, again, are radiation, chemotherapy, surgical management. Appendamomas, that often can be treated with surgery, radiation, sometimes chemotherapy in the younger children. And the malignant gliomas outside of DIPG, it's surgical, radiation as well.

And it's interesting, chemotherapy has been tried for a lot of these malignant gliomas in children. And it's still not clear whether there are really good backbone chemotherapeutic regimens to really improve outcomes. Certainly, the drug of choice in adult malignant glioma like glioblastoma, temozolomide has yet really to be proven to have the same effectiveness in childhood high-grade glioblastomas.

So, I hope that gives a little bit of an overview of our tumors and the management that we have for them.

Melanie Cole (host): Well, it certainly does and thank you so much for that. And I'm glad that you brought up the difference between glioblastomas in adults and gliomas in children. And as you've spoken about management strategies, Dr. Sayour, and some of the challenges to treating these in children and for developing effective therapies in clinical trials, I'd like you to speak about some of the novel treatments and what you're doing at UF Health Shands Hospital. Tell us a little bit about immunotherapies. I know that they've been looked at for adults, but what about for children? And if they have, how have been the results?

Dr. Elias Sayour Sayour: Thank you for that question. So, as I mentioned at the intro, because we've gotten better at treating other cancers, brain tumors are now the leading cause of death from cancer in children. And so, we really do need new therapies. We are starting to see some newer regimens arise. This is some of the targeted therapies that we're employing in low-grade gliomas. Certainly, we're trying to adapt this to some of the higher grade gliomas and hoping for therapeutic effect.

Here at UF Health Shands Hospital, we have a particular interest in immunotherapy. Immunotherapy is largely the ability to recruit the immune system to fight on a patient's behalf and kill their own cancer. The challenge, of course, with immunotherapy is what to target. Sometimes that isn't clear. A lot of these cancers, especially in children, unlike adult cancers, these tend to be more developmental tumors, meaning genes that during development that are supposed to turn off, turn back on and can lead to some of these tumors that we just discussed. And so, that doesn't really look foreign to the immune system. And so, being able to stimulate an immune response can be a challenge.

But here at the University of Florida UF Health Shands, we've really come up with some novel methods to do just that, to actually sensitize a response against a patient's individual tumor. And we use really the RNA technology that people now all over the world are familiar with in light of the COVID-19 vaccines. We take RNA, which is just information. Really that's all RNA is, is it's information, but we take it from a patient's tumor and we can load it into a vaccine using lipid particles, lipid nanoparticles. We can actually take the master cells from the patient, the master immune cells called dendritic cells, and we can load that personalized information from a patient's tumor in the form of RNA into their master cells, those dendritic cells, and give that as a vaccine. We can also take the patient's other immune cells called T-cells, which are the army members and basically educate them outside the patient's body and return them to fight the tumor.

So, we have trials for each of these things right now in children with malignant brain tumors, dendritic cell vaccines, T-cell therapies, mRNA vaccines using lipid particles. And there have been cases of patients who have had some pretty remarkable responses to these interventions and we are hoping to learn from those patients in terms of why those patients had such a good outcome to really broaden the impact of this work to other people.

Melanie Cole (host): This is a fascinating topic and such a hopeful time in your field, Dr. Sayour. As we wrap up, I'd like you to speak to other providers about when you feel it's important that they refer to the specialists at UF Health Shands Hospital, what sets you apart, really makes you unique, and anything else you'd like the key takeaway to be. Whether it's precision medicine and gene sequencing, whatever you would like to speak about, summarize that for us.

Dr. Elias Sayour Sayour: Yeah. Thank you for that question. I think that a child with a brain tumor really mandates multidisciplinary care, multidisciplinary expertise. We have that here at UF Health Shands Hospital. That doesn't just entail a surgical intervention or radiation. It really mandates, especially for many of these malignant tumors, innovative approaches, whether it's a new clinical trial, whether it's consortias. We're a part of pediatric consortias that include the Pacific Pediatric Neuro-Oncology Consortium, the Pediatric Brain Tumor Consortium. And those consortiums allow us to reach out to regional experts, allow us to offer the latest and greatest clinical trials for some of these diseases.

For some of these tumors like glioblastoma in a child, or diffuse pontine glioma in a child, really, clinical trial is a standard of care. It really is. Because these diseases are so refractory, these are really standard approaches for management of children. And so, being at a place that can offer not just one, but several different trials and have experts kind of identify what might be the best trial for a particular child, I think is critical. And all these cancers are different, even if they have the same name, diffuse pontine glioma, glioblastoma. Each person's tumor is different and it is personalized to them. And so, being at a place that can understand the personalization of an individual's tumor, come up with therapies that are personalized and trial options that are unique to that individual really mandates that you have a portfolio of different trials with a network of connections to national experts that can be offered to patients and families in a way that's best for them and their individual tumor. And that's the kind of expertise that we have here that we can offer our patients. And certainly, I think that this is a responsibility we have to all of our region in North Central Florida. But because of the expertise here, we draw patients nationally and internationally.

Melanie Cole (host): Well, you certainly do, and I can hear your passion and compassion in your voice, Dr. Sayour. Thank you so much for joining us today and sharing your incredible expertise and the exciting advancements in the field.

To learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to refer your patient or to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters. That concludes today's episode of UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole. Thanks so much for joining us today.