Transcription:
Surgery for GERD

Andrew Wilner, MD (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center and division director of neurology at Regional One Health Memphis, Tennessee.

Today, we're discussing rare cancers that affect the brain and spinal cord. Because these tumors are rare, they may not have been subject to formal clinical trials. Consequently, proven treatment options may be limited. Thankfully, we continue to hear about innovations in diagnostics and treatment that bring hope to patients.

Joining me today is Dr. Rimas Lukas. Dr. Lukas is an Associate Professor of Neurology and specialist in neuro-oncology at Northwestern Medicine. He's going to share with us some of the advances in clinical care for patients with rare cancers of the central nervous system. Welcome, Dr. Lukas.

Rimas Lukas, MD: Thank you for having me.

Andrew Wilner, MD (Host): Dr. Lukas, thanks for joining us. Please tell us about any recent clinical trials or research at Northwestern Medicine that has yielded any innovative outcomes. Is there any research that you're particularly excited about?

Rimas Lukas, MD: Sure. I'm particularly excited about clinically-oriented research that we have for rare central nervous system tumors. And we're honored to be part of the National Cancer Institute Rare Central Nervous System Phase II Clinical trial. This is a study that's looking at an immunotherapeutic approach across a wide range of different tumor types. And the rationale behind this is, as you had mentioned earlier in the introduction, that many of these rare central nervous system tumors do not have dedicated clinical trials to help guide us in the optimal management. And this is a way for us to evaluate the potential efficacy of a therapeutic modality within the context of this.

Now, within the context of this study, we're looking at a PD-1 antibody, and this is a way to pull the brakes off the immune system to try to help treat these tumors. This is an approach that's been very successful in other types of tumors, melanoma, for example, as well as others.

Andrew Wilner, MD (Host): So I think it's interesting that, you know, when I was in medical school, which was a way back, we did radiation therapy, we did chemotherapy. I don't know that we did a lot of immunotherapy, but I'm hearing more and more about that. Can you give me some background what that has to do with CNS tumors?

Rimas Lukas, MD: Sure. So, you know, the immune system does a great job taking care of problems throughout the body. And it includes cleaning up messes. So when somebody has an infarction, it cleans up what's happened there and then allows it all to scar up afterwards. When somebody develops a tumor, it helps get rid of that tumor potentially. Effective in other parts of the body, but as you're well aware, the central nervous system is a relatively immunoprivileged site, right? And so we have dampened immune activity in the central nervous system for good reasons, because if we don't have that dampened immune activity, we can have an overreaction and then lead to autoimmune diseases of the central nervous system, multiple sclerosis being one common example.

In turn, we've had to kind of overcome some hurdles in trying to use immunotherapy within that central nervous system, but it's still something that holds for us a lot of promise. And so it's, I think, something that, you know, we're excited to hopefully see in our patient populations, the same kind of sustained responses that we've seen in other diseases outside of the nervous system.

Andrew Wilner, MD (Host): You know, as a neurologist myself, I do see patients with CNS tumors but, you know, not all that often. And I guess it never really occurred to me that it was difficult to make a diagnosis sometimes even when you have a brain tissue, you know, as a biopsy. So could you tell us about I've heard of methylation profiling and any other types of sort of testing that you do that's new that helps make a more precise diagnosis?

Rimas Lukas, MD: Sure. No, I'd be happy to hear. I think, you know, the way that we had looked at tumors in the past was histologically, right? And so the experienced neuropathologist looks at it under the microscope and says this is tumor type A or it's tumor type B or it's tumor type C based on the histology and the immunohistochemical staining that's associated with it.

What's interesting is a lot of the time they were right, you know, right? So 90% of the time they have the appropriate diagnosis, but we still saw a decent amount of noise or a decent amount of variability with regards to outcomes. So when we look at Kaplan-Meier survival curves, for example you know, you can see from one study to another that there are different outcomes in survival. And some of this is probably driven by misdiagnosis. So something that histologically looked like one tumor type, but at the subcellular level or the molecular level looked very different.

And so one of the big revolutions in neuropathologic diagnosis has been the advent of what's called molecular neuropathology. And this is I think probably one of the most rapidly evolving parts of the field. And in the beginning, you know, it was an evaluation of specific genes, looking for a mutation in this gene or a fusion of this gene adjacent to another one. And then over time, there was a broader panel of genes that were evaluated.

And now, routinely in our clinical practice, we're evaluating all tumors with a very large panel of over 500 genes, to take a look and see what kind of abnormalities are present there. And this has benefit from a diagnostic perspective, meaning that one tumor type may have this set of abnormalities, this set of mutations, et cetera, that we'd expect to see. And then it also has benefit from a therapeutic perspective. And so there are certain types of mutations or fusions for which there are drugs available that we can utilize in treating those tumors. So that's the next generation sequencing aspect and that's become embedded in the diagnostic classification system. So in 2016, the World Health Organization included some of these molecular characteristics into their classification system. And now in the 2021 iteration of the World Health Organization Classification System for Central Nervous System Tumors, this is even more well-codified.

Now, after the next generation sequencing, we've begun to see sort of the beginning of a revolution in what's called DNA methylation profiling. And so the way that I think of it and the way I explain it to my patients is the next generation sequencing is looking at the genome itself. Right? So it's looking at the script and it's looking for abnormalities within the script. The methylation profiling is looking at the abnormalities that are written in the margins of the script. As an example, we all have the same genome throughout our various tissues in the body. And the genome in your skin is expressing different proteins within the cells than the genome in your heart or in your brain, et cetera. And the way that it does that is by turning on and off various genes. And it does that by methylating the promoters for them. And so you can look at different tissues and have distinct fingerprints to say this is this type of tissue versus that type of tissue. And then you can even go further and do the same thing for tumor types.

And what's exciting about it for us is it really helps us nail down the diagnosis, particularly for these more esoteric tumors. And within the more common tumor groups, say like glioblastoma, we can see that there are actually various distinct subtypes of glioblastoma based upon the DNA methylation profiling with slight variability in the outcomes. But for these rare tumors, this is I think a really fantastic tool for us to have available. And so right now in our program, we're doing this universally for all of our central nervous system tumors

Andrew Wilner, MD (Host): you know, that's fantastic. And I want to thank you, because it's been at least 30 years that I've been trying to figure out why, you know, some patients with a glioma, there's always these outliers, you know. A malignant glioblastoma, everybody dies in three years and then there's one guy that lives 10 years, right? Like, you know, how is this possible? And I think he just explained it. I mean, it wasn't luck, right? It was that there was an underlying difference, subtle difference that now with advanced technology, we can actually detect, diagnose, prognosticate and maybe even therapeutically impact. I think, you know, that's an amazing story. Well, to make all this happen, I guess you need a team. Do you have a team there at Northwestern, you know?

Rimas Lukas, MD: Correct. Yeah. No, this is definitely a team effort. And I think, you know, for me as a medical neuro-oncologist, my job is to play quarterback and manage the day-to-day patient care. Make sure they see the right person at the right time, the neurosurgeon at this time, the radiation oncologist this time, and then manage the chemotherapeutic and other systemic therapeutic aspects of their care. We are extremely lucky to have really a superstar neuropathologist team. And it's led by Dan Brat, who's the Chair of Pathology here and by Craig Horbinski, who is the Chief of Neuropathy and is an expert molecular neuropathologist. So we're really lucky to have individuals like this who are able to bring these cutting edge technologies to our institution, the DNA methylation profiling being a nice example, and then being able to conduct cutting edge research, you know, on their own and also collaborate with others. So I think, you know, all of that makes my life a lot easier and I think it substantially improves the quality of our patient care.

Andrew Wilner, MD (Host): And even patients who are not at Northwestern, if I understand correctly, their physicians can send their slides or samples to Northwestern for more precise diagnosis if they live far away. Is that right?

Rimas Lukas, MD: Correct. Yeah. So there's definitely the ability to have pathology review. And, you know, I think from our perspective, we would like to utilize all the bells and whistles that really kind of help us flesh out what tumor type it is. And for me, that would be the next generation sequencing as well as that DNA methylation profiling. And I think the two platforms are very complementary to one another. So the DNA methylation profiling really helps solidify what tumor type or subtype this is. And then the next generation sequencing also helps support that and then also looks for potential targetable abnormalities. And when we're thinking about some tumor types, like glioblastoma, the amount of targetable abnormalities are limited. If we're looking at some of these rarer central nervous system tumors, we actually might have a higher likelihood of having a positive hit for something that can then be utilized in the clinical management.

Andrew Wilner, MD (Host): Dr. Lukas, that's really interesting. Is there anything else that you'd like to share with us today?

Rimas Lukas, MD: Sure. You know, I think I would like to highlight some of our rare central nervous system tumor specialized programs. So one that I think we're excited about is our low-grade glioma program. And this is typically a disease that's skewed towards younger patients and the pre-surgical planning, et cetera, are very important in trying to maintain a good long-term functionality. I'd also probably highlight our VHL or Von Hippel-Lindau disease program, which as a neuro-oncologist focuses on hemangioblastoma, low-grade tumors, but ones which can be associated with a significant amount of morbidity. And I also want to highlight our chordoma program. And so chordomas are tumors not of the nervous system, but adjacent to the nervous system, and they can cause substantial morbidity by impinging on that nervous system and having carefully planned out surgical approaches as well as proton therapy approaches for radiation can make a very big impact with regards to morbidity as well as survival. So I think, you know, we have the opportunity to really have very sub-specialized care for our patient population. So I'm excited to be supportive of all those programs.

Andrew Wilner, MD (Host): Well, that's great. I think that's a very exciting resource that we're finally making some real headway in brain tumor and related tumor treatment Dr. Lukas, I want to thank you very much for this great discussion on advances in neuro-oncology and for joining us on Better Edge.

Rimas Lukas, MD: Thank you. It's my pleasure.

Andrew Wilner, MD (Host): And that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/neuro to get connected with one of our providers.

Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. For updates on the latest medical advancements and breakthroughs, you can follow us on your social media channels. I'm your host, Dr. Andrew Wilner. Thanks for listening.