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A new vision in the lab and in the clinic

Since the discovery of X-rays in the 19th century, new imaging technologies have helped physicians peer into the causes of disease and provide better clinical care.

When Dennis Spencer, M.D., recalls his first days as a neurosurgeon in the early 1970s, he doesn’t wax nostalgic about the way he imaged a patient’s brain. “We weren’t that far from Harvey Cushing,” he says, referring to Yale’s renowned “father of neurosurgery” and X-ray pioneer, who died in 1939.

Spencer then had two X-ray imaging tools at his disposal. One was angiography, introduced in 1927 but still widely used, in which an injected dye illuminates a patient’s blood vessels on X-ray. The other was pneumoencephalography, a painful invasive procedure dating back to 1919 that involves draining fluid from the brain and injecting air into its ventricles to prepare for an X-ray. “It was a pretty crude field at the time,” says Spencer, chair and the Harvey and Kate Cushing Professor of Neurosurgery.

This antediluvian period ended by the mid- to late-1970s with the advent of computer-assisted tomography (CAT or CT) X-ray scans, which enabled Spencer to see blood, soft tissue, and some tumors noninvasively. Imaging capabilities accelerated in the 1980s with the development of magnetic resonance imaging (MRI or MR), which provides even sharper internal images without exposing the patient to radiation; and then positron emission tomography (PET) imaging, which detects changes at the cellular level. These and other devices—boosted by increasingly powerful computers and often used in combination—have radically improved the detection and treatment of disease.

Today Spencer can remove or stimulate parts of the brain responsible for intractable Parkinson or epilepsy and leave vital parts intact. “I can put an electrode within two millimeters of any part of the brain,” he says.

Yale clinicians and scientists are seizing on the imaging boom to improve patient care. Advanced techniques have moved from the lab to the clinic and the operating room and have become key tools for quicker, more accurate diagnoses and better outcomes. Surgeons can now see inside a patient’s body in three dimensions in real time while they operate. Imaging technology can identify the places to avoid during brain surgery, whether a cancerous prostate should be left alone, or whether a breast mass is normal or cancerous. Imaging modalities can not only make surgery more precise but may also help a patient sidestep an operation or biopsy altogether.

“When I started, I thought I was getting in on the tail end of the developments of MR,” says R. Todd Constable, Ph.D., professor of diagnostic radiology. “It turns out, 23 years later, that it hasn’t matured yet.” Constable, a physicist, is often called on to find the best device (or devices) for other specialists, and his team uses those modalities to develop a clinical map of the inside of a patient’s body. Everyone thought CT scanning “was done” by 1990, he says, but the development of multi-detector, multi-slice imaging extended its warranty. “There’s still a revolution in imaging for modalities we discovered years ago that we thought were mature,” Constable says.

From X-ray to fMRI

The first great step in medical imaging came in 1895, when Wilhelm Röntgen took an X-ray of his wife’s hand, famously displaying her bones and wedding ring. Cushing, then only 26 and a newly minted M.D., recognized the significance of the device and put X-rays to clinical use within months. But X-rays went only so far because they allowed medical professionals to see bones or teeth but little else.

Ultrasound, which creates images through sound waves and is familiar to any expectant parent, came into use in the 1950s. Constable says ultrasound didn’t—and still doesn’t—deliver clear images, but it has the advantage of being safe, affordable, and nowadays, highly portable. The next huge advance came in the 1970s, when the London-based Electric and Musical Industries developed the CT scan. The CT scan was the first to deliver X-ray images of the body in cross sections, and the images could be viewed either as individual slices of bread or an entire loaf. By the next decade, MRI, which uses magnetic fields and radio waves to capture images of internal organs, began providing even clearer shots of soft tissue.

Further breakthroughs in medical imaging came from unexpected sources—computer graphics and the film industry. “We can all thank Hollywood and the gaming industry,” says Xenios Papademetris, Ph.D., an associate professor of diagnostic radiology, who prepares surgeons for procedures by mapping a patient’s brain or other body part ahead of time. Graphics cards were “designed to let kids play games,” he says. “We’re using them to do other things.”

Constable works with Spencer and other researchers by preparing images for their research or surgical procedures and says that the technology has made Yale a leader in providing surgical treatments for patients with epilepsy who don’t respond to drugs. “Things are moving from the research lab—where we can image these different aspects of brain function or brain metabolism or what have you—and into the sort of real-time intraoperative mapping,” Constable explains. When, for instance, epilepsy patients are being prepared for surgery, they’ll first get an fMRI. “When you speak in the magnet, or read, we can isolate your language cortex,” Constable says. During an operation, a surgeon can see where that spot is and knows not to “cut that cortex because [the patient’s] not going to be able to speak afterwards.”

Epilepsy is Spencer’s specialty, and the technology helps him track the origin of seizures. He’ll cut open a patient’s skull and—with the help of people like Constable and Papademetris—implant a grid over the brain, leaving it there for 10 days while he monitors brain activity. During that time the patient’s epilepsy drugs are withdrawn, and the monitor lets Spencer see which parts of the brain are initiating seizures. Information is collated with the patient’s CT scans to find the problem spot, which Spencer can locate on the axes of the grid as a player might do in a game of electronic Battleship. Electrical stimulation, again guided by imaging, identifies such critical function regions as language. He’ll go back into the patient’s brain and resect diseased areas, sparing function.

Two operating rooms at Smilow Cancer Hospital at Yale-New Haven have MRIs specially built for surgery, including the world’s first combination intraoperative MRI/endovascular suite. There, Spencer’s neurovascular faculty uses the MRI and a biplane angiography device that produces 3-D images of the blood vessels in the brain. He says the improved images have drastically changed the treatment of brain aneurysms. Ten years ago, 90 percent of arterial bulges were controlled by placing clips on them. Today, aneurysms are more often secured internally by coils inserted by a microcatheter—a safer, less-invasive method—and the use of clips has fallen to between 30 and 40 percent.

Preventing false positives

While Spencer often uses imaging as a tool during an operation, Liane Philpotts, M.D., chief of breast imaging at Yale, will happily employ it to prevent a false positive. In addition to ultrasound and MR, she says that Yale has the best mammography technology yet: digital breast tomosynthesis.

Tomosynthesis, approved by the Food and Drug Administration in 2011 after trials at Yale and four other medical centers, is the first technology to deliver three-dimensional images in mammography. When used in conjunction with traditional 2-D images, tomosynthesis cuts down false positives by 30 to 40 percent, Philpotts says. It has also increased the rate of cancer detection by up to 20 percent. “Tomosynthesis is a game-changer,” she says. “It’s a win-win.”

Traditional mammograms can’t always distinguish cancerous cells from harmless ones. This lack of clarity is especially problematic in patients—usually younger women—with dense breasts, which have more glandular than fatty tissue. “Fat we can see through,” Philpotts explains. Glandular tissue, however, appears as white on an image, as do cancer cells. “This is one of the limitations of mammography.”

Philpotts shows the difference in the images of a patient who underwent both a standard mammogram and tomosynthesis. The procedures are roughly the same for the patient: the breast is compressed in the machine and the 3-D device takes a series of images through an arc of 15 degrees, which are then reconstructed as 1-millimeter slices instead of just a top or side image of the entire breast as is done in a routine mammogram.

Philpotts calls up a 2-D image of a whole breast on one of two adjacent monitors. It shows a mass of white in the middle. Philpotts is suspicious of the mass but the image’s blurriness won’t let her draw any conclusions. She switches the display on the monitor, which then shows the individual images, like a high-tech zoetrope. Each slice shows an area deeper within the tissue. “It’s as if you can see through the breast,” she says. As Philpotts progresses, she spots a telltale spidery lesion that indicates cancer.

In 2009, the U.S. Preventive Services Task Force (USPSTF), a group of outside advisors to the Department of Health and Human Services, recommended that women over 50 have mammograms every two years instead of yearly. Citing the cost of false positives and the radiation younger women are exposed to, the panel suggested that women in their 40s not get screened unless they are in a high-risk group. Those recommendations were “controversial,” Philpotts says, conflicting with those of groups like the American Cancer Society, which continued to back yearly mammograms for women between 40 and 49.

Philpotts thinks that 3-D imaging can help bridge the gap between the conflicting recommendations. A team at Smilow Cancer Hospital reviewed the mammograms of 14,684 patients and found that the cancer detection rate was 5.7 per 1,000 patients in those who underwent both 2-D and 3-D screening compared to 5.2 per 1,000 among those who had only a standard mammogram. Subsequent ongoing data collection has shown an even greater difference in cancer detection. Moreover, 54 percent of those whose cancer was detected with the combined imaging had dense breasts; of those whose cancer was identified by 3-D imaging only, 21 percent had dense breasts. In 2009, Connecticut became the first state in the nation to mandate that women be notified if a mammogram shows that they have dense breast tissue and that their insurance pay for additional screening.

With 3-D imaging, Philpotts said, the risk of false positives is reduced. “We’re saving on the costs of unnecessary diagnostic workups and possibly biopsies.”

At the start of her career 20 years ago, “when you had a finding, you had to go to the OR,” Philpotts says, but today “very few patients need to be taken to surgery.” The 3-D machine can reduce the number of callbacks, but those who must return also benefit from better imaging, which guides doctors through a real-time core needle biopsy to remove small pieces of dubious tissue. Ultrasound is used as a complement to mammography to find the extent of disease, if any, since cancerous cells appear dark on an ultrasound image. Patients fear a biopsy, but they’re relieved by the minimal invasiveness of the procedure.

Seeing what can’t be imaged

Improved imaging systems are also helping Yale physicians treat cancers specific to men. Prostate cancer is even harder to find than cancer of the breast, because the prostate is the only solid organ in which cancer cannot be imaged. Ultrasound—the modality that guides clinicians to the prostate—alone cannot see tumors, says Peter Schulam, M.D., director of the Cancer Center’s Prostate and Urologic Cancer Program. His team, like those of other specialists, uses a combination of imaging modalities that work better together than separately.

When Schulam arrived at Yale from UCLA last year, he recruited a team of doctors, engineers, and radiologists. He also brought a 3-D imaging navigation system called the Artemis Device, which he says is the best available to identify and monitor the progress of prostate cancer.

“Every man with prostate cancer doesn’t need to be treated,” Schulam says. “The question is: How do you differentiate?” Prostate cancer kills roughly 30,000 American men every year—more than any other malignancy except lung cancer, according to the American Cancer Society. Most men diagnosed with the disease, however, die of some other cause.

High levels of prostate-specific antigen (PSA) may signal cancer, but an enlarged but healthy prostate can also raise PSA levels. In 2012, the USPSTF recommended against PSA screening for cancer, saying that men are too often treated when the disease isn’t causing symptoms. CT scans aren’t beneficial in detecting possible cancer, so doctors increasingly use MRI. “The problem is that once you see something suspicious on an MRI, it’s hard to biopsy” because the powerful magnets prevent the use of needles, Schulam says. A prostate biopsy is often educated guesswork, with doctors taking a dozen or so passes with a 1-millimeter-thick needle into the walnut-sized gland. Not only are biopsies often painful procedures and recovery can lead to such complications as sepsis, but “you can miss cancer,” Schulam says. “Or you can detect cancer but not know the volume of cancer.”

Because prostate cancer generally progresses very slowly, treatment options range from radiation or removal of the prostate to watchful waiting, in which doctors take no significant action unless the diseased organ causes problems. Active surveillance—careful monitoring for signs that the disease is progressing—is a relatively recent approach that falls somewhere in between. It is usually recommended for men at low risk of developing symptoms from the disease. Artemis, which combines MR and ultrasound images to improve the detection and treatment of prostate cancer, is the key tool in the image-guided approach to active surveillance of the disease.

Artemis uses a multiparametric MRI—which also measures chemical concentrations and blood flow in tissue—to identify regions of the gland that may be cancerous. “The machine takes the MRI image and an ultrasound image and puts them together in a 3-D model,” says Preston Sprenkle, M.D., a urologist on Schulam’s team. The real-time ultrasound feature then “helps us guide where our needles go,” so biopsies aren’t as blind as they have been in the past.

The team can then determine how diseased the prostate is through what’s called a Gleason score—which predicts whether the cancer will grow and spread to other organs—and what action comes next. Men with a low Gleason score can prevent or postpone unnecessary radiation therapy or a prostatectomy, which can leave patients incontinent or impotent. “If you lose one or both of those, your quality of life is dramatically changed,” Sprenkle says.

Artemis promotes active surveillance because it “records exactly where the biopsy was taken from,” Schulam says. When the team members examine the gland a second time, they have a superimposed image so “we can biopsy the exact same place as before. If something changes, you intervene such that you haven’t lost your window of opportunity to achieve cure.”

A revolution in every field

Advances in imaging, from X-rays to CT scans to fMRI, have taken a lot of the guesswork out of diagnosis and treatment. They have reduced inaccuracies in testing, spared patients anxiety from false positives, and improved outcomes. Spencer is happy with the progress he’s seen since his early days when neurosurgical imaging was in its infancy. “Imaging is important to everything we do every day,” he says. “It’s revolutionized every field. Our understanding of the brain—and our understanding of brain disease and the future of treating it—is just so tied to our imaging.”