The tumor war

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A CALIFORNIA BRAIN SURGEON WIELDS FORMIDABLE NEW WEAPONS AS HE BATTLES ON THE FRONT LINES OF

If her brain tumor had shown up 10 years ago, Melinda Schuler would not have had much of a chance. Few doctors would even have tried to remove the malignant growth, located in her right frontal lobe, that had already taken over one-sixth of her cranium, pushing her brain down and to the left. Leave it alone, and the cancer would keep compressing useful tissue inexorably, robbing the patient of speech, movement, consciousness, life itself--all within months. Try to cut it out, and there would be the risk of taking too little, leaving cancerous tissue to grow again, or taking too much, causing profound and irreparable brain damage.

It was fortunate for Schuler that the tumor was discovered in 1997 rather than in 1987. In the intervening decade, brain surgery advanced dramatically, enabling doctors to refine their operating techniques enormously with the aid of more sophisticated medical technology. Today they can chart a far safer passage to tumors hidden deep in the brain. But, more to the point for Schuler, Dr. Keith Black, the man who stands over her exposed brain with scalpel in hand, is one of the world's most talented brain surgeons, known for working with the most difficult of brain tumors.

PHOTO (COLOR): His malignant tumor removed, a grateful Steven Schulman, right, calls Dr. Keith Black "God." Such encomiums make the doctor uncomfortable)

Of the 5,000 or so neurosurgeons working in the U.S. today, 4,900 concentrate mostly on the spine and deal on average with only five or six brain tumors a year. Of the 100 who routinely work inside the skull, perhaps 50 specialize in blood-vessel repairs rather than tumors. Only the remaining 50 can be considered brain-tumor specialists, averaging 100 surgeries annually. Along with a handful of others, Black averages more like 250 such operations a year. His referrals come not only from the U.S. but from Europe, the Middle East, South America, Japan and Australia as well. A tumor that is inoperable for the average neurosurgeon is not necessarily inoperable for Black.

That's how Melinda Schuler ended up on Black's operating table at the UCLA Medical Center. (This past summer Black became director of a new neurosurgery institute at Cedars-Sinai Medical Center, also in Los Angeles.) The neurosurgeon in Reno, Nev., who performed the original biopsy would not touch the tumor, which was sitting right in the middle of her motor area. He could have taken it out but feared that Schuler would be left paralyzed. "Most of the tumors I see are like this," Black says in his soft Southern voice.

Black focuses his attention exclusively on Schuler's exposed brain and the voracious tumor that threatens it. An hour and a half earlier, he had drilled a series of holes into Schuler's cranium, then connected the dots with a surgical jigsaw. He had lifted out an oval-shaped piece of skull, then cut through and peeled back the dura mater, a thick membrane that protects the brain and spinal cord.

Navigating methodically, Black now divides the tumor from the normal brain, cauterizing severed blood vessels as he goes. He cuts all the way around the edge of the tumor, gradually detaching its mass. Fifteen minutes later, he lifts the bulk of Schuler's cancer out of the hole he has made and places it in a stainless-steel bowl. "Call the tumor guys to come down and get a specimen," he orders. Another piece of the tumor will be sent to Black's own lab while he goes back in to clean up the cavity.

Schuler's death sentence has been postponed, perhaps for years. By the following day, she will be walking the halls. Not surprisingly, she will feel deep gratitude. This is not uncommon; most of Black's patients exhibit an awe for his skills that borders on worship. "You're God," exclaims another patient on being told his tumor has been removed. "No, I'm not," Black replies, quietly but firmly. He gets such comments frequently, and they make him very uncomfortable. No one is more acutely aware than Black of the perils of the physician-God complex. A lot of his patients would like him to play God and tell them they will never be sick again. They look for it in his eyes. He is therefore careful not to promise too much, not to let his eyes promise too much, even when there is hope.

PHOTO (COLOR): Before cutting, Black maps out a brain tumor to make certain he doesn't slice into vital tissue. If the cancer is too intertwined with "eloquent brain," he'll try another course

And hope is a rare commodity when it comes to brain cancer. Although successful treatment of tumors like Schuler's malignant astrocytoma can give patients three to five years more, the mean survival period for people with the most common and deadly brain cancers (glioblastomas) is about five months without surgery--and about a year and a half even after successful operations, according to one study. Like Black, neurosurgeons at top cancer centers around the country are working on a variety of experimental techniques that they hope will improve patients' survival. Any one of them may turn out to be a winner.

What makes Black unique is not immediately apparent. He has a steady hand, a remarkable intelligence, an ability to concentrate on the task in front of him, and a lot of experience at removing tumors. But plenty of surgeons can claim these. It is something else entirely that distinguishes Black from most of his colleagues: an absolutely unshakable devotion to a single task. Says Dr. Edward Oldfield, chief of surgical neurology at the National Institutes of Health: "This is the unique feature of his career--the way he is using rather striking advances in basic science in the application of new treatments." Keith Black is fighting an all-fronts war against brain cancer.

The war began when Black was still in college, at the University of Michigan. By the time he got there, he had already made it clear that he was no ordinary young man, most likely because he came from no ordinary family. His father, Robert Black, was principal of the segregated Boykin Street Elementary School in Auburn, Ala., during the George Wallace era. When he could not integrate the student body, he integrated the staff instead and began teaching French to fourth-graders. When his sons wanted to swim in the all-white community pool, he told them to do it. And when young Keith showed an early fondness for dissection, he brought home a cow's heart from the local slaughterhouse. "He was the ultimate educator," Black recalls. "He instilled in us an attitude that there is nothing that you cannot do."

When Black was in eighth grade, his family moved to Cleveland, Ohio, and he started hanging out in the labs at Case Western Reserve University. By high school, he was performing organ transplants and heart-valve replacements in dogs. At 17 he was a semifinalist in the national Westinghouse science competition for his research on the damage done to red blood cells in patients with heart-valve replacements. That year he was accepted in a University of Michigan six-year program that offered degrees in biomedical science and medicine.

From the beginning, Black was fascinated by the brain. "It's the most beautiful thing you will ever see," he says, "not so much on the surface but when you get around the optic nerves and the cranial nerves and around the brain stem. There's a saying: If you want to understand the artist, you study his art. If you want to understand God, you study the anatomy of the brain." (Black is a Lutheran and attends church with his wife, UCLA urologist Carol Bennett, and their two children.)

Initially, he was drawn to try to understand the mystery of consciousness itself--to fathom the connection between the physical brain and the elusive thing called the mind. He plunged into neuroanatomy, neurochemistry, neurophysiology, philosophy, religion and mysticism--until it began to dawn on him that he was "learning more and more about less and less." He started to question whether science could understand consciousness at all, and halfway through medical school he returned to more pragmatic pursuits in the lab.

Black was still interested in the brain, however. His lab work included studies on how a number of substances, including barbiturates and naturally occurring body chemicals called prostaglandins--and, because it promotes the production of prostaglandins, aspirin as well--could be helpful in preventing or limiting the damage caused by stroke.

Then in 1981 he read an article that identified a class of compounds called leukotrienes. These natural body compounds promote swelling after injury by making blood vessels leaky. Black knew that a major limiting factor in fighting brain tumors was the blood-brain barrier, which prevents cancer-killing drugs from entering brain tissue from the bloodstream. If leukotrienes made vessels leaky, he suspected, then these or similar compounds might help break through that barrier.

From then on, he was hooked. Brain cancer was such a powerful, tricky and deadly enemy that Black decided he would try to conquer it. It was an ambitious goal, even for a man who would later be dubbed "Indiana Black" for his daring exploits outdoors--skydiving, whitewater rafting and trekking through the Himalayas--while maintaining a demanding schedule in the operating room and the research labs. Black has been on safari and rafted down the Zambezi River in Zimbabwe. He has climbed Tanzania's Mount Kilimanjaro and made it to 17,000 ft. on Manaslu, in Nepal.

In short, Black has a penchant for taking on challenging tasks that require meticulous planning and multiple skills--and succeeding. His approach to brain cancer is no different. He began training as a neurosurgeon for the stressful, delicate job of cutting into the living brain. But he also plunged with equal dedication into work in the laboratory, where he studied the basic biochemistry of tumors.

Black is best known for his discovery that bradykinin, a natural body peptide, is highly effective in opening the blood-brain barrier by making capillary walls leaky--the way leukotrienes do, he says, only to a greater degree. "The fantastic thing about bradykinin," says Black, "is that it does not open the barrier to the normal brain--only to tumors." By using RMP-7, a synthetic version of bradykinin, Black's team has been able to focus chemotherapy drugs right on the tumors, increasing the effective dose as much as 10-fold. Crucial to RMP-7's success, however, is the development of more effective chemotherapy drugs against brain cancer.

DIAGRAM: TWO NEW WAYS TO ATTACK TUMORS - 1 The blood-brain barrier stops cancer-killing drugs in the bloodstream from entering brain-tumor cells Bradykinin, a naturally occurring body chemical, opens the barrier by making capillary walls leaky A bonus with bradykinin is that it affects only capillaries that feed tumors, not vessels that supply the normal brain: 2 Tumors produce TGF-beta, a substance that helps them grow and makes them invisible to the immune system When TGF-beta antisense is inserted into a tumor, the production of TGF-beta is turned off

Black is also working on an entirely different experiment for treating tumors. Cooperating with molecular biologist Habib Fakhrai, he is trying to enlist the patient's own immune system to attack brain cancers. Tumor cells produce a substance called TGF-beta (transforming growth factor-beta) that both fuels their own growth and tricks the immune system into ignoring their presence. Using genetic engineering, Fakhrai has come up with a genetic "switch," called TGF-beta antisense. When inserted into a tumor cell's genetic machinery, the antisense turns off the cell's ability to produce TGF-beta. Injected into patients, these deactivated cells work like a vaccine by becoming immediate targets of the immune system, which simultaneously kills off other tumor cells circulating in the body. In a current clinical trial, one patient's cancer has been arrested, with four more treatments to go. Twelve more patients are being selected for an upcoming trial.

Black now wants to turbocharge TGF-beta gene therapy with dendritic cells, white blood cells that identify foreign proteins for destruction. He proposes to harvest dendritic cells from a patient's blood, expose them to cancer proteins in a test tube and reinject them. The cells would then point out the now familiar proteins to the immune system's killer T cells, which would track them down like bloodhounds that have been exposed to an escaped convict's dirty laundry. "We can completely eradicate glioblastomas in rats using this strategy," says Black. "We want to get these treatments out into clinical practices as fast as we can."

The reason for such urgency is that no matter how carefully a surgeon cuts out a malignant tumor, the few stray cancer cells that are inevitably left behind will begin to grow again. TGF-beta and dendritic cells, or any one of a dozen other treatments under investigation by Black and others, could lead to the true cure for brain cancer that is Black's long-term goal.

Meanwhile, as new treatments go through the painstaking testing and approval process, Black is determined to do his absolute best with the tools at hand, using creative surgical techniques to get at cancers once considered all but intractable. For example, clival chordomas, deadly tumors that grow at the base of the skull, could be reached only by cutting through the entire brain, which left patients devastated. As one of the pioneers of skull-base surgery, Black now removes clival chordomas by going up through the nasal passage, bypassing the brain entirely. His patients go home without any loss of function (known to doctors as a "deficit").

Surgically, Black is as aggressive as his foe but also excruciatingly careful. During his residency, Black recalls, "we would get postoperative scans, and you could actually see the physical damage where the neurosurgeon had used instruments to pull the brain back to expose the tumor. I never touch the brain. It's sacred. It's a concept I try to teach the residents. The whole goal is to extract the tumor without disturbing the normal brain. It's as if the brain is asleep and you want to sneak in and remove the tumor and never wake the brain up."

In fairness to his predecessors, Black has more going for him than just a pair of gifted hands and a veneration for the human brain. He also has access to powerful technology that was unavailable a decade ago. By the time he is ready to apply his scalpel to a tumor, Black has already mapped out the cancer in extraordinary detail. He knows before going in, more precisely than ever, where the boundary lies between malignancy and "eloquent brain," the clusters of cells responsible for speech, perception, motor activity and language.

In Schuler's case, Black began his reconnaissance several days before the actual operation with a technique known as functional magnetic resonance imaging. As in conventional MRI, the patient lies inside a chamber while a powerful electromagnet creates X-ray-like pictures of the inside of the brain. In this case, though, the pictures are taken as the patient deliberately performs actions such as moving limbs, speaking or doing mental tasks. With each action, the blood flows to whatever part of the brain is in use at that moment and "lights up" the relevant areas on the MRI picture.

The result is a detailed image of where eloquent brain tissue is located (it is slightly different in each patient). If there is a safe corridor into the tumor and if the cancer does not contain vital brain tissue, it is O.K. to operate. So far, Black has used functional MRI for surgical planning on 30 patients. "If the MRI said it was safe to remove the tumor," he says, "none of those patients turned out to have deficits postoperatively."

When he first began using it, standard MRI could make only two-dimensional images of the brain. A couple of years ago, however, the fda approved a 3-D version in which a computer combines up to 50 separate slices to create a single image of brain and tumor; the surgeon can view the tumor from any angle to plan the surgery in minute detail. Not only that-- when the neurosurgeon touches any point on the head with the tip of a penlike device called a stereotactic wand, a marker appears at the corresponding spot on the MRI image, displayed on a nearby screen. "In theory," Black says, "you can follow the dotted lines and just cut the tumor right out."

You could, that is, if the brain stayed put, but drugs used to prevent swelling can cause it to shrink slightly. Besides, the brain has a consistency something like that of Jell-O; when tissue is cut, things can shift. So for a last survey of the terrain before removing the tumor, Black uses techniques called somatosensory-evoked potentials and direct stimulation to check on the boundaries between tumor and eloquent brain.

The techniques are like two sides of a coin. In the first, Black applies a mild electric current to a part of the body--the wrist, for example--and then touches electrodes to exposed brain areas. It is like an electrician testing a circuit: wherever he picks up current, he knows he has a live connection, indicating that the tumor is entwined with eloquent brain and cannot just be cut out. Otherwise, he is touching inert tumor tissue. Conversely, with direct stimulation, Black applies the current to the tumor and sees if the body twitches in response.

All these tools have revolutionized neurosurgery but, just as in his lab work, Black keeps pushing to improve them. He is advising a student, for example, on a project aimed at essentially bringing functional MRI into the operating room in real time. This would permit a surgeon to re-image the brain constantly during surgery in order to observe the changing geography of the brain as the operation progresses. Black is also seeking advances in noninvasive surgery, used when a tumor is so deeply embedded in eloquent tissue that it cannot be cut out. Surgeons now use focused beams of X rays to kill cancer tissue, but because these devices rely on radiation to destroy tumors, they can be used only sparingly. And because tumors killed this way take months to die, there is no way for the surgeon to know during treatment if he has got all of the tumor.

Instead, Black began to use radio waves, which cook the cancer to death right away. A few years ago, he developed a treatment that uses an MRI-guided radio-wave probe to reach into a tumor. The procedure can be performed under local anesthesia on an outpatient basis and be repeated as needed. Now Black wants to eliminate even this mildly invasive probe with something he calls the MedArray. The prototype, which Black expects to be ready for trials next year, looks like an MRI with microwave antennas lining the chamber. Using the MRI's images, the MedArray computer maps out the cancer, then directs the antennas to cook it like a rump roast. Because the entire process is controlled by computers, it is conceivable that the surgeon will not have to be at the scene of an operation. Just imagine, says Black, "the patient is lying in the MedArray machine in Nairobi. The MRI image is sent to a surgeon at Johns Hopkins, who directs the machine to destroy the tumor while he's getting feedback via the Internet. And then the patient walks out."

PHOTO (COLOR): Black ponders his next task at the neurosurgery institute at Cedars-Sinai Medical Center in Los Angeles. His recent move there was a big coup for the all-new facility

Armed with such powerful weaponry to kill the main body of the enemy, and backed up by new therapies like TGF-beta antisense to hunt down straggler cells, Black believes the audacious course he set for himself in medical school may be attainable. Along with other top neurosurgeons, he may yet find a way to defeat--not just hold off--malignant brain tumors.

If that occurs, old-fashioned cutting may become obsolete, and surgeons like Black could be put out of business."That would be fantastic," he says. But a man like Black would not go meekly into retirement. What would he do instead? "I guess I'd go back and try to define consciousness," he speculates. "That's what I would really love to do." He would, in short, move from a seemingly impossible crusade to one that promises to be even more difficult. For anyone who knows Keith Black, that would come as no surprise.

PHOTO (COLOR): Black's medical skills are backed by tools ranging from X rays to powerful diagnostic and treatment devices like 3-D MRI scanners and noninvasive tumor killers

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By MICHAEL D. LEMONICK REPORTED BY ARNOLD MANN/LOS ANGELES

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