Ian Parney, MD, PhD
Ian Parney, MD is Associate Professor of Neurosurgery at the Mayo Clinic in Rochester Minnesota.
Reflecting my role as a neurosurgeon and clinician-scientist, my research group focuses on three main themes:
Improving Glioma Surgery
We seek to develop and rigorously test techniques facilitating aggressive surgical resection for gliomas while maintaining or improving patient safety. These include integrating functional imaging (functional MRI, diffusion tensor imaging tractography) into image-guidance systems and intra-operative MRI, correlating this with intra-operative electrophysiological mapping, and pursuing novel strategies such as fluorescence-guided resection.
Understanding Glioblastoma Immunology
Glioblastomas suppress immune responses both locally within the tumor and systemically throughout the body. We seek to understand the cellular and molecular mechanisms underlying this immune suppression. We are testing the general hypothesis that a tightly regulated cellular network made up of glioblastoma cells, glioblastoma-infiltrating monocytes, circulating myeloid-derived suppressor cells, and regulatory T cells underlies glioblastoma-mediated immunosuppression. The roles of immunosuppressive factors expressed by many of these cells (B7-H1, TGF-ß, PGE2, IL-10) are being investigated. Model systems include in vitro interactions between cultured human glioblastoma cells (including glioma stem cells) and human leukocytes, as well as a humanized SCID/nod mouse model reconstituted with human hematopoietic stem cells and bearing human glioblastoma stem cell xenografts. As much as possible, experiments are carried out with tumor cells and leukocytes obtained from patients undergoing glioblastoma surgery at Mayo Clinic, highlighting the translational nature of these studies.
Developing Effective Glioblastoma Immunotherapies
Based on our increasing understanding of glioblastoma immunology, we seek to develop effective strategies to reverse glioblastoma-mediated immune suppression and stimulate anti-tumor immune responses. We are particularly interested in optimizing tumor vaccine timing compared to standard therapies (which can alter glioblastoma-mediated immunosuppression), manipulating dendritic cell vaccines to maximize their immunostimulatory properties, and targeting critical cell populations such and glioblastoma stem cells. In addition to studies carried out with the in vitro and in vivo models systems described above, we are fortunate to have access to the Mayo Clinic Human Cell Therapy Laboratory. This Good Manufacturing Practices (GMP) facility is capable of producing clinical grade cellular tumor vaccines. Thus, we are able to readily translate our laboratory findings back to the clinic.
University of Alberta
University of Alberta
Grey Nuns Hospital
University of California, San Francisco
Malignant brain tumors
Brain tumor immunotherapy
200 First Street SW
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There is a obviously a lot of variation, but many patients will have had a CT scan of the head performed at their initial presentation followed quickly by a MRI scan that gives greater anatomic detail. In my own practice, I like to get a MRI with the appropriate sequences for frameless stereotactic planning (image-guidance) in the operating room. Depending on the situation, we may also obtain special MRI scan sequences such as perfusion sequences or functional MRI scans to look for motor or speech function. We also sometimes perform experimental imaging like F-DOPA PET scans to learn whether these new types of imaging provide helpful new information for surgical planning.
Simply put, intra-operative MRI (iMRI) is a combination of a MRI scanner and an operating room. In many ways, it is the ultimate form of image-guided surgery. Image-guidance refers to frameless stereotactic techniques used by neurosurgeons to help guide surgery. In my operating room, we get a MRI before surgery after placing a series of stickers on a patient’s scalp. The images are sent to a computer in the operating room that is hooked up to a couple of infra-red cameras that can see the stickers and can also see a wand that I can point at the patient’s scalp. The computer then shows me a 3D reconstruction of the MRI where ever I point the wand. It’s a little like a GPS for the brain. Now, if you have ever seen a MRI with a large, bright brain tumor on it, you might wonder why this is necessary. “Gosh Doc, isn’t it obvious? Just take out the white bit.” Well, the truth is that it can sometimes be very difficult to tell where a brain tumor ends and normal brain begins, despite the MRI appearance. Image guidance can be very helpful. “OK”, I hear you saying, “but why do you need an intra-operative MRI? Couldn’t you just get a regular MRI with the stickers before surgery and use that?” Well, yes we could and often we still do. The problem is that the brain will shift as we take a tumor out, particularly if the tumor is large or if we have drained a large amount of spinal fluid. At the end of the surgery when we really want to know if we’ve removed the entire tumor, our image-guidance system is at its least accurate. An intra-operative MRI is an answer to this by allowing us to re-register our image-guidance during surgery. In my operating room, we typically get a MRI scan before starting surgery in the morning, take another one during surgery to up-date our guidance system once the bulk of the tumor is gone, and get another MRI at the end to see how we did and make sure there are no signs of complications.
Unfortunately, glioblastomas cells are very good at shutting the immune system down. Glioblastoma cells themselves produce a number of proteins and other factors (e.g. TGF-β, PGE2, B7-H1) that inhibit killer T cells and other potent immune cells. Furthermore, glioblastoma cells seem very good at attracting other white blood cells called macrophages and converting them into cells called myeloid-derived suppressor cells (MDSC) that inhibit immunity even further. Finally, the immune suppression in glioblastoma patients is not limited to the tumor environment alone. Glioblastoma patients have increases in circulating immune suppressing cells like MDSC and regulatory T cells throughout their body. While this might seem depressing, we are beginning to understand these immune suppressing networks in glioblastoma patients and figuring out how to reverse them. Although the science on this is pretty early, it seems that one of the most important factors may turn out to be one of the simplest: get rid of as much tumor as possible. Surgery to remove as much visible tumor as possible appears to be a potent way to reverse much of the glioblastoma-mediated immune suppression, at least temporarily. This is one reason why many glioblastoma immunotherapy clinical trials start with surgery to remove all visible tumor before any immune treatment is given.
Immunotherapy (harnessing the immune system to attack and kill tumor cells) has been a goal for cancer scientists studying glioblastoma for many years. Although still experimental, results from a number of clinical trials are looking increasingly promising. Some immunotherapies involve medications that stimulate the immune system in general and others involve transfer of white blood cells that have been stimulated in the lab. However, most glioblastoma immunotherapies have focused on vaccines designed to stimulate patients’ immune systems directly to attack tumor cells. These are therapeutic vaccines given to treat tumors, not preventative vaccines like those given to prevent infectious diseases. Some target a specific protein or proteins present on tumor cells but not normal cells. Others are directed against collections of proteins obtained from patients’ own tumors. Frequently this involves dendritic cells, a potent white blood cell population that is critical for stimulating immune responses, that are grown in the lab from patients blood and then given back as a vaccine after mixing them with tumor proteins. In the future, immunotherapy may be a standard part of glioblastoma treatment but, for now, it remains experimental.
When I started medical school twenty-three years ago, it was an accepted fact that we were born with all the neurons we would ever get and that these neurons could never be replaced. Well, it turns out that this is not true. The brain has a normal population of immature, slowly dividing stem cells that can differentiate and form neurons and other normal brain cells when the conditions are right. This was a game-changing finding that had huge implications for many diseases and injuries affecting the brain. One result of this discovery is that it has become clear that brain tumors like glioblastomas contain cells that look an awful lot like normal neural stem cells. These Brain Tumor Stem Cells (BTSC’s) are relatively immature but dividing cells that can differentiate to look a little like astrocytes (connective tissue cells in the brain), neurons, and other brain cells and form the bulk of a tumor. They are not true neural stem cells because, like all cancer cells, they lead to disordered and uncontrolled growth. However, a lot of evidence suggests that BTSC’s may be the key population of cells that drive the growth of tumors like glioblastomas. Not only that, BTSC’s are resistant to many of our standard treatments like radiation and chemotherapy. This means that a therapy that successfully targets BTSC’s might be much more effective at treating glioblastomas than our current treatments. Many researchers around the world are working very hard to develop treatments like this.
Every patient, young or old, needs to be evaluated individually to decide what the most appropriate treatment is for them. This is based on a number of factors, including the size and location of their tumor, the exact pathological diagnosis, the severity of their symptoms, and their overall health. In some cases, older patients may have a number of other medical conditions that might adversely affect their overall health and could make it difficult for them to tolerate the most aggressive forms of surgery, radiation, or chemotherapy. However, this is NOT universal and must be judged on a case by case basis. We have recently published studies that have suggested that appropriately selected older malignant glioma patients do as well with aggressive surgery, radiation, and chemotherapy and get just as much benefit from it as younger patients. The key is deciding who is likely to get the most benefit.
Although many elderly patients are good candidates for aggressive treatment, there is no question that other illnesses and overall health in some older patients would make it difficult for them to tolerate the most aggressive surgery, radiation, or chemotherapy treatments. Thankfully, there are still many options for treatment available for these patients. For example, almost all patients are able to tolerate a biopsy to establish the diagnosis even if a bigger operation to remove the tumor is seems ill-advised. There is strong evidence to suggest that a shorter three week course of radiation is tolerated better and has similar benefit to the standard six week radiation treatment in elderly patients. Finally, modern chemotherapy agents such as temozolomide are generally better tolerated than earlier types of chemotherapy and can be considered in older patients, though these patients must be followed closely as they are more likely to have side effects from temozolomide than the general population.
This is a great question that gets at the heart of a key difficulty in brain surgery. How can we possibly operate in the brain without hurting people? Some of this is based on the knowledge of brain anatomy that has been worked out over hundreds of years. For example, we know things like that each brain hemisphere controls function on the other side of the body, that motor function originates in the back part of the frontal lobe, or that the occipital lobe contains the visual cortex. The problem is that brain tumors can distort normal anatomy, making it more difficult to be certain where function resides. Furthermore, some functions can have highly variable representation in different people. For example, speech can involve either the left or right hemisphere with between one to five critical areas for speech in the frontal, temporal, or parietal lobes. To help sort out this potential minefield, we use a number of strategies. Functional MRI scans (fMRI) that measure differences in regional blood flow to brain areas when patients perform specific tasks like moving a limb or generating a list of words) can give an overview of functional localization that can be incorporated into image-guidance technology. However, fMRI accuracy is limited to about 1 cm. To get a more accurate assessment, the gold standard is electrophysiological mapping at surgery. This typically involves placing an electrical stimulator on the surface of the brain and seeing how brain function is affected. For motor mapping, we look for twitching on the other side of the body. For speech mapping, we see if we can interrupt speech by putting the stimulator on the brain. To do this, patients have to be awake. This is possible because the brain itself does not have any sensation. We need local anesthetic to make the scalp numb, but are able to operate in the brain itself without causing any discomfort!