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BY MARYANN B. BRINLEY Savana Delgado turned four in August and Peter Carmel, MD, played an important part in her reaching this milestone. "All serendipitous events are carefully prepared for," says Carmel, Director of the Center for Pediatric Neurosurgery at UMDNJ-New Jersey Medical School. In fact, like any modern tale of near disaster, Savana’s survival from a brain tumor more than a year ago has an imperative, repeating refrain: living happily ever after may seem serendipitous but is actually carefully prepared for in the right medical setting. More than luck was on Savana's side. The Brain Tumor Program at the Neurological Institute of New Jersey, led by Carmel and a team of highly trained specialists, was on Savana’s mother's professional radar screen before April 28, 2002. After all, Doris Cortes-Delgado works in the UMDNJ publications office on the Newark campus. Names in UMDNJ news are her business. Yet, on that spring weekend when her toddler became violently ill and Cortes-Delgado was crazed with anxiety while being transferred from suburban hospital to hospital, one name in particular just wouldn’t come to her. What was it? Stress wouldn’t let her think straight. Finally, in a call to a co-worker, she pleaded, "What is that doctor’s name? You know, that expert in pediatric neurosurgery? I can’t remember it." "You mean Dr. Peter Carmel," she was told. After being alerted to Savana's situation in another hospital and studying her MRI, Carmel, an internationally renowned professor of neurological surgery, said, “Let’s transfer her here immediately.” By here, he meant UMDNJ–University Hospital (UH). On May 2nd, Carmel successfully removed a large pilocytic astrocytoma, a generally benign, slow-growing tumor, that had been sitting on Savana’s brain stem since birth. Smiling when he emerged from seven hours of surgery, Carmel could announce with confidence, “Everything’s fine. I got it all”…a pronouncement not easily made by all neurosurgeons in every hospital. Moreover, this type of non-infiltrating tumor tends to stay in the area where it starts and is not likely to spread or recur. Finely-tuned skills in each new approach, new equipment and chemotherapeutic options are essential to making miracles like Savana’s happy birthday come true. Not all medical centers are financially or technically equipped to remain on the cutting edge of technology essential for brain tumor treatment. “Nothing that we do now in neurosurgery is being done the way I was initially trained,” Carmel points out. The practice of neurosurgery has changed so dramatically in the last 30 years that he believes, “It’s clear neurosurgery has to be centralized” geographically speaking. “Equipment is just part of the reason. It also takes a higher expertise to do this kind of surgery. I’m a pediatric neurosurgeon in academic medicine. All I do is pediatric and skull based surgery.” Others on his staff are just as accomplished and specialized. "Ours is a pretty unique service of extremely high quality. Our faculty will publish three medical books this year. Michael Schulder’s Handbook of Stereotactic and Functional Neurosurgery just came out. Allen Maniker’s atlas of peripheral nerve surgery will be here early next year and Bob Heary’s book on spine deformities is due next summer."The NJMS neurosurgical staff is also averaging 18 published articles a year. These are experts setting the standards others will follow. To spotlight some innovations in brain tumor treatment from personal perspectives, Healthstate interviewed Carmel, as well as Michael Schulder, MD, NJMS associate professor, neurosurgery, co-director, stereotactic radiosurgery and director of the Center for Image-Guided Surgery; Charles J. Prestigiacomo, MD, NJMS assistant professor, neurological surgery and radiology with specialities in cerebrovascular and endovascular surgery; Jonathan S. Harrison, MD, NJMS associate professor, hematology and oncology; and Charles Cathcart, MD, director of radiation oncology and co-director of the Stereotactic Radiosurgery Center. Peter Carmel: When he was chief neurosurgical resident at the College of Physicians and Surgeons at Columbia University in New York, Carmel would watch his mentor, an esteemed neurosurgeon, take 20 percent of his craniotomy procedures back to the operating room after surgery if they didn't wake up well that night or the next day. “It was easier to open the brain flap again to see if there was a blood clot causing a problem than it was to get the information any other way,” he explains. With all the sophisticated imaging advances available now, Carmel can hardly imagine that opening the brain a second time to check visually was easier and less risky for the patient. “This has all taken place in my active lifetime.” Powerful MRI and CT scanners produce images with such unprecedented speed and clarity that there is never any reason to operate so blindly. “We used to have only angiography and something called pneumoencephalography, both of which were cumbersome and real risks to the patient.” In particular, the Polestar N-10, UH’s intraoperative MRI system, used during surgery to image the brain, “has remarkably changed the treatment of brain tumors.” UH was the first hospital in North America, and the second in the world, to have a Polestar with its .12 tesla magnetic fields, optical probe, and infrared cameras. This machine can be wheeled from a magnet-shielded closet, hooked right onto the end of a normal operating table and worked via a control mouse. Use of computer buttons comes naturally to a generation of neurosurgical residents raised on computer games. Polestar arrived two years ago and "the first head scanned in that machine was mine," Carmel says smiling, recalling jokes made by younger staffers about the atrophy on his scan. More than 200 brain tumor cases at UH have benefited from the Polestar and in at least two ways. First, visually differentiating between tumor and brain tissue can be difficult so the Polestar allows a surgeon to tailor the operation to areas of the brain that may have been missed before. Remnants of tumor left behind are likely to grow back. “We are doing better with slow-growing benign tumors than with malignant glial tumors but there is evidence that increasing removal of certain glial tumors will lead to better results. Polestar tells me whether or not there is any tumor left, based on what can be seen on the scan,” Carmel explains. In fact, in a recent procedure on a 23-month-old girl whose family had been told elsewhere that her tumor was inoperable, “I thought all of the tumor was removed and did one final scan. In the coronal view, there was more tumor sitting right next to the ventricle. I had looked at that spot and didn’t see anything. So I used the navigation from the magnet and the infrared camera, and with that information, I removed the last bit of tumor.” Polestar also helps compensate for the inevitable shift in the brain. Yes, the brain actually moves during surgery because it is surrounded by cerebrospinal fluid and will "always sag toward the direction of gravity." Thus, pre-operative MRI, CT and cerebral angiography (X-rays of the brain’s blood vessels) can provide valuable diagnostic information but using that data alone for guidance during a procedure is “very limited because of this brain shift.” With the Polestar, “we now get incredibly good removals of tumors that would have been only partially removable.” Michael Schulder: "Brain surgery is more accurate, more thorough and has advanced exponentially in navigation techniques and intraoperative imaging," says Schulder, who received his training in neurosurgery at the Albert Einstein College of Medicine, finishing in 1988. Radiosurgery, for instance, was in its infancy back then and "has since become ubiquitous and an absolutely routine part of neurosurgical treatment." Stereotactic radiosurgery is a non-invasive operation that precisely delivers focused, multiple beams of radiation to a single point on a tumor site while avoiding healthy tissue. Moving to this phase of non-invasiveness is a real technological triumph. “There is no need for hospitalization with stereotactic radiosurgery for a brain tumor,” Schulder says. “It can be done as an outpatient in your street clothes.” After performing hundreds of these procedures, he is amazed when comparing radiosurgical patients to those who must undergo open surgery for tumor removal. Even the older metal stereotactic frame, which was attached to the patient’s skull for reference while three-dimensional images were projected onto a computer to guide the surgeon, is now gone from many radiosurgeries. Frameless stereotactic surgery relies on “wands,” or infrared markers, and offers the same precision without any need to attach a metal frame to someone’s skull. Radiosurgery doesn’t have a 100 percent cure rate, is not appropriate for all brain tumors and patients do require careful follow-up. Yet, for the treatment of certain benign and even some malignant tumors, “there are statistically-defined likelihoods of tumor control and no short-term complications,” he says. “Patients walk out at the end of the day and some go back to work the next. That’s astounding. "I've seen an interesting turn of the wheel,” Schulder says. Near the end of his residency, there was a trend toward very aggressive surgical therapy, especially for skull-based tumors. The goal was to take out all tumor tissue, at all cost." We figured we had one chance and if the patient woke up with a little slur in speech or unable to swallow, it was okay because otherwise, the tumor would have killed him.” The pendulum has swung away from that direction. “We want people to come out of surgery at least as good as when they went in. At the end of the day, we still have to show that people are being cured more often, living longer and in better shape as a result of surgery for brain tumors.” Take functional MRI (fMRI) and Functional Image-Guided Surgery (FIGS) which map the brain not just for its anatomy, but for areas in the body under its control. No modern neurosurgeon likes to tamper with “eloquent” realms of the brain that control senses, motor function or speech. To avoid damage to delicate areas, fMRI and FIGS are fundamental. While being scanned, a wide-awake patient is asked to perform a series of activities or movements, such as reading a list or tapping fingers. The areas which correlate to these actions will light up on the scan and create a safe map for navigation. “I just removed a low grade glioma (a large category of primary tumors that originate in the glial, or connective, cells). The lesion looked like it might be inside the motor cortex but the fMRI said it was in front of that critical area so it was safe to do the procedure,” Schulder says. He and his team have demonstrated how fMRI can even be done in the operating room itself with the Polestar iMRI system. For the future, as exciting and beneficial as new surgical technology is, Schulder looks past the equipment, especially for curing primary tumors that arise in the brain itself. In the end, treating tumors locally, or simply taking them out, especially the kind which infiltrate brain tissue, can be "maddening because they can recur locally, even after expanding the area of treatment using brachytherapy (implanting radioactive seeds), radiosurgery, or implanted chemotherapy." The future of successful brain tumor strategies is in the patient’s own biology, according to Schulder. More research in chemotherapies and immune treatments using vaccines and gene manipulation hold the answers. "It’s just too easy to get caught up in the tools," he concludes.
Charles Prestigiacomo: Prestigiacomo would agree. “The technical exercise of taking out a brain tumor can be invigorating and satisfying but what’s your final endpoint?” A measurement in quality of life is more important than a radiographic cure, an X-ray or MRI showing no tumor. Neurosurgeons make judgement calls and experience teaches them how much is too much, he says. “You walk a fine line, balancing delicately, always focusing on the mantra, ‘First do no harm.’” For a mother of seven children, ages three months to 11 years, that meant not taking out all of the extra-axial (extrinsic) tumor wrapped around her brain stem and spinal cord. “This was one of the strangest ones I’ve seen,” Prestigiacomo recalls. Shuffling and in need of a walker last fall, she could barely lift her arm to feed the baby. “She just wanted to live longer to take care of her kids.” Completely removing this tumor was out of the question, so Prestigiacomo decided to peel back just enough to give her brain room. Using evoked potential testing and fMRI, he could touch nerves attached to tumor tissue to see how “this very delicate, high priced real estate” in her central nervous system would be affected before he cut anything. As a result, “I could just shave it off without disturbing anything.” She’s walking, caring for her children and undergoing chemotherapy. This ability to map and navigate precisely to a tumor, while avoiding normal brain tissue, has been transformed since he graduated from Columbia University's College of Physicians and Surgeons and then completed his neurosurgical residency in 2000. “When I started my residency, which wasn’t that long ago, we used a frame around the head and a coordinate system to outline where we wanted to go. A little tube, or catheter, was gently placed to the depth the computer indicated. Then, we presumed the tumor was there at the tip of the catheter.” These are presumptions no longer needed in neurosurgery. What else is changing
in brain tumor treatment is the ability to get chemotherapeutic agents
past the blood-brain barrier (that wall of nerves and cells protectively
surrounding the brain membrane yet reducing the ability of drugs to work
therapeutically). NJMS/UH was one of four sites nationwide Blood vessels feed brain tumors which tend to “pop back up,” he explains. Because the same blood vessels which lead to primary tumors also go to the brain, you can’t just cut off all supply. His goal is to employ specific chemical antigens that will only recognize and attach to tumor tissue (not just locally but throughout the brain), using a catheter snaked up through the body and into the brain. Using vectors like this intra-arterial targeted therapy is “not out of the question and will certainly come up within my generation.”
Jonathan
Harrison: Harrison is an expert in neuro-oncology. Even amidst the din of the UH cafeteria, he can effectively pull an initiate through the histological features of brain tumors, how their pathology is being revolutionized, which arsenal of chemicals is capable of tumor anti-angiogenesis (formation of blood vessels) activity and the most current avenues of investigation in brain tumor treatment. He’s even employing thalidomide, originally developed as a sedative but banned in 1960 after it was discovered to cause birth defects in babies born to mothers who took it for morning sickness. “I’ve used it in 10 to 15 brain tumor cases because it inhibits vascularity (blood flow to the tumor) and retards tumor growth. There are traditional chemotherapies that cross the blood-brain barrier and there are also new natural compounds being investigated.” One comes from tree bark: irinotecan. “We now know that genetic mutations underlie some brain tumors and we are developing molecularly targeted therapies.” Even the type of tumor (astrocytoma) which grew inside Savana has a mutated growth factor related to a specific genetic family. This is promising news. Schulder, the brain surgeon, calls Harrison’s chemotherapeutic touch, the kitchen sink approach. “I’d prefer to say an all-fronts attack,” Harrison says. Regardless of the terminology, the results are sometimes gratifying. “We generally assess brain tumor patients by their neurological function and their survival.” Take, for example, the 28-year-old man with an ordinarily fatal glioma. The patient, who was originally treated by Schulder, had a recurrence in September 2002, and his prognosis didn’t look good. Harrison employed one of his all-fronts chemical attacks. “I gave him thalidomide, chemozolamide, carboplatin, irinotecan and anti-nausea medication. He came in every two weeks. At first, he couldn’t speak, walk, or use his right arm. With treatment, he became dramatically better, speaking fluently and walking. All but one of his cranial nerve deficits disappeared. Because the tumor knocked out his left cranial nerve, he can’t abduct his left eye. But on the MRI, the tumor was gone about a year after he began chemotherapy.” The young man’s mother, who was devastated watching her son deteriorate, was very happy. “You can imagine, of course, that the patient is very, very appreciative,” Harrison says. Median survival has been poor for these glioblastomas-only in the range of nine to 12 months. “Now, which of these drugs is responsible? We don’t know. Only standardized, randomized research will tell us. For this disease, there is a case for using everything.” Happy Birthday, Savana A picture of a beautiful toddler comes up on Peter Carmel’s computer screen. “She's 100 days away from surgery and that’s what makes this work so wonderful,” he says. In August, when they sang “Happy Birthday” at Chuck-E-Cheese, the crowd of party-goers clapping for Savana Delgado were equally and wonderfully awed.
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Advances In Brain Tumor Surgery 
